CLCN3 chloride voltage-gated channel 3 [Homo sapiens (human)] - Gene

Summary

Official Symbol: CLCN3provided by HGNC
Official Full Name: chloride voltage-gated channel 3provided by HGNC
Primary source: HGNC:HGNC:2021
See related: Ensembl:ENSG00000109572 MIM:600580; AllianceGenome:HGNC:2021
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: CLC3; ClC-3; NEDSBA; NEDHYBA
Summary: This gene encodes a member of the voltage-gated chloride channel (ClC) family. The encoded protein is present in all cell types and localized in plasma membranes and in intracellular vesicles. It is a multi-pass membrane protein which contains a ClC domain and two additional C-terminal CBS (cystathionine beta-synthase) domains. The ClC domain catalyzes the selective flow of Cl- ions across cell membranes, and the CBS domain may have a regulatory function. This protein plays a role in both acidification and transmitter loading of GABAergic synaptic vesicles, and in smooth muscle cell activation and neointima formation. This protein is required for lysophosphatidic acid (LPA)-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. The protein activity is regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in glioma cells. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]
Expression: Ubiquitous expression in brain (RPKM 27.7), colon (RPKM 19.9) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 4q33

Exon count:: 18

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	4	NC_000004.12 (169620578..169723673)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	4	NC_060928.1 (172980359..173083792)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	4	NC_000004.11 (170541729..170644824)

Chromosome 4 - NC_000004.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

ClC-3 silencing mediates lysosomal acidification arrest and autophagy inhibition to sensitize chemo-photothermal therapy.
Title: ClC-3 silencing mediates lysosomal acidification arrest and autophagy inhibition to sensitize chemo-photothermal therapy.
Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders.
Title: Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders.
Swelling-activated ClC-3 activity regulates prostaglandin E2 release in human OUMS-27 chondrocytes.
Title: Swelling-activated ClC-3 activity regulates prostaglandin E(2) release in human OUMS-27 chondrocytes.
ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect in human stomach adenocarcinoma.
Title: ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect in human stomach adenocarcinoma.
Suppression of CLC-3 reduces the proliferation, invasion and migration of colorectal cancer through Wnt/beta-catenin signaling pathway.
Title: Suppression of CLC-3 reduces the proliferation, invasion and migration of colorectal cancer through Wnt/β-catenin signaling pathway.
ClC-3 induction protects against cerebral ischemia/reperfusion injury through promoting Beclin1/Vps34-mediated autophagy.
Title: ClC-3 induction protects against cerebral ischemia/reperfusion injury through promoting Beclin1/Vps34-mediated autophagy.
that ClC-3 expression in cancer cells induces mediating multidrug resistance by upregulating NF-kappaB-signaling-dependent P-glycoprotein expression involving another new mechanism for ClC-3 in the development of drug resistance of cancers
Title: Chloride channel-3 mediates multidrug resistance of cancer by upregulating P-glycoprotein expression.
Starvation-induced autophagy is up-regulated via ROS-mediated ClC-3 chloride channel activation in the nasopharyngeal carcinoma cell line.
Title: Starvation-induced autophagy is up-regulated via ROS-mediated ClC-3 chloride channel activation in the nasopharyngeal carcinoma cell line CNE-2Z.
The expression and function of CLC-3 were promoted after XRCC5 overexpression, and the promotion effects were reversed by the CLC-3 knockdown. The mechanistic study revealed that knockdown of XRCC5 suppressed the binding of XRCC5 to the CLC-3 promoter and subsequent promoter activity, thus regulating CLC-3 expression at the transcriptional level by interacting with PARP1.
Title: Overexpression of CLC-3 is regulated by XRCC5 and is a poor prognostic biomarker for gastric cancer.
the expression of ClC-3 chloride channel in chondrosarcoma was examined.
Title: Overexpression of ClC-3 Chloride Channel in Chondrosarcoma: An In Vivo Immunohistochemical Study with Tissue Microarray.

Submit: New GeneRIF Correction See all GeneRIFs (55)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Neurodevelopmental disorder with hypotonia and brain abnormalities MedGen: C5561977 OMIM: 619512 GeneReviews: Not available	not available
Neurodevelopmental disorder with seizures and brain abnormalities MedGen: C5561979 OMIM: 619517 GeneReviews: Not available	not available

EBI GWAS Catalog

Description
Biological insights from 108 schizophrenia-associated genetic loci. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

SHGC-50487 (e-PCR)
- UniSTS:18944

SHGC-59606 (e-PCR)
- UniSTS:51456

G19897 (e-PCR)
- UniSTS:70948

D4S2506E (e-PCR)
- UniSTS:70949

A002B34 (e-PCR)
- UniSTS:70950

SHGC-51377 (e-PCR)
- UniSTS:15986

SHGC4-1562 (e-PCR)
- UniSTS:10873

SHGC-51266 (e-PCR)
- UniSTS:83333

STS-R65780 (e-PCR)
- UniSTS:63887

D4S2510E (e-PCR)
- UniSTS:64655

SHGC-67333 (e-PCR)
- UniSTS:83857

SHGC-59697 (e-PCR)
- UniSTS:60566

SHGC-59505 (e-PCR)
- UniSTS:3785

SHGC-50268 (e-PCR)
- UniSTS:63442

RH91155 (e-PCR)
- UniSTS:85475

D4S2677 (e-PCR)
- UniSTS:68331

SHGC-59636 (e-PCR)
- UniSTS:27884

D4S2563E (e-PCR)
- UniSTS:68081

SHGC-59347 (e-PCR)
- UniSTS:44787

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables PDZ domain binding	IDA Inferred from Direct Assay more info	PubMed
enables antiporter activity	ISS Inferred from Sequence or Structural Similarity more info
enables chloride channel activity	IDA Inferred from Direct Assay more info	PubMed
enables chloride channel activity	TAS Traceable Author Statement more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables voltage-gated chloride channel activity	IBA Inferred from Biological aspect of Ancestor more info
enables volume-sensitive chloride channel activity	IMP Inferred from Mutant Phenotype more info	PubMed

Process	Evidence Code	Pubs
involved_in adult locomotory behavior	IEA Inferred from Electronic Annotation more info
involved_in chloride transmembrane transport	IDA Inferred from Direct Assay more info	PubMed
involved_in endosomal lumen acidification	TAS Traceable Author Statement more info	PubMed
involved_in negative regulation of cell volume	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in phagocytosis, engulfment	IEA Inferred from Electronic Annotation more info
involved_in photoreceptor cell maintenance	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of reactive oxygen species biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in regulation of pH	TAS Traceable Author Statement more info	PubMed
involved_in synaptic transmission, GABAergic	IEA Inferred from Electronic Annotation more info
involved_in synaptic transmission, glutamatergic	IEA Inferred from Electronic Annotation more info
involved_in synaptic vesicle lumen acidification	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
is_active_in GABA-ergic synapse	IDA Inferred from Direct Assay more info	PubMed
is_active_in GABA-ergic synapse	IMP Inferred from Mutant Phenotype more info	PubMed
is_active_in Golgi apparatus	IBA Inferred from Biological aspect of Ancestor more info
located_in Golgi apparatus	IDA Inferred from Direct Assay more info	PubMed
located_in Golgi membrane	IEA Inferred from Electronic Annotation more info
located_in axon terminus	IEA Inferred from Electronic Annotation more info
located_in cell surface	NAS Non-traceable Author Statement more info	PubMed
located_in cytoplasmic vesicle	IDA Inferred from Direct Assay more info	PubMed
is_active_in early endosome	IBA Inferred from Biological aspect of Ancestor more info
located_in early endosome	IDA Inferred from Direct Assay more info	PubMed
located_in early endosome membrane	IEA Inferred from Electronic Annotation more info
located_in endosome membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in external side of plasma membrane	IDA Inferred from Direct Assay more info	PubMed
is_active_in glutamatergic synapse	IDA Inferred from Direct Assay more info	PubMed
is_active_in glutamatergic synapse	IMP Inferred from Mutant Phenotype more info	PubMed
located_in intracellular membrane-bounded organelle	IDA Inferred from Direct Assay more info
located_in late endosome	IDA Inferred from Direct Assay more info	PubMed
located_in late endosome membrane	IEA Inferred from Electronic Annotation more info
located_in lysosomal membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in membrane	HDA more info	PubMed
located_in membrane	TAS Traceable Author Statement more info	PubMed
located_in phagocytic vesicle	IDA Inferred from Direct Assay more info	PubMed
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in recycling endosome	ISS Inferred from Sequence or Structural Similarity more info
located_in ruffle membrane	IEA Inferred from Electronic Annotation more info
located_in secretory granule	IDA Inferred from Direct Assay more info	PubMed
located_in specific granule	IDA Inferred from Direct Assay more info	PubMed
is_active_in synaptic vesicle	IBA Inferred from Biological aspect of Ancestor more info
located_in synaptic vesicle	IDA Inferred from Direct Assay more info	PubMed
is_active_in synaptic vesicle membrane	IDA Inferred from Direct Assay more info	PubMed
is_active_in synaptic vesicle membrane	IMP Inferred from Mutant Phenotype more info	PubMed
located_in vesicle membrane	IDA Inferred from Direct Assay more info	PubMed

General protein information

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Preferred Names: H(+)/Cl(-) exchange transporter 3

Names: chloride channel 3; chloride channel protein 3; chloride channel, voltage-sensitive 3; chloride transporter ClC-3

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_029731.2 RefSeqGene

Range

5002..108097

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001243372.2 → NP_001230301.1 H(+)/Cl(-) exchange transporter 3 isoform a

See identical proteins and their annotated locations for NP_001230301.1

Status: REVIEWED

Description

Transcript Variant: This variant (a) lacks an in-frame exon in the middle coding region, compared to variant b. The resulting isoform (a) lacks an internal segment, compared to isoform b.

Source sequence(s)

AA780395, AC106878, AK304362, DA102505

Consensus CDS

CCDS58932.1

UniProtKB/TrEMBL

B3KXK0

Related

ENSP00000353857.3, ENST00000360642.7

Conserved Domains (2) summary

cd03684
Location:136 → 615

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

cd04591
Location:638 → 776

CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
NM_001243374.2 → NP_001230303.2 H(+)/Cl(-) exchange transporter 3 isoform c

Status: REVIEWED

Description

Transcript Variant: This variant (c) lacks two exons from the 5' end but has an alternate 5' exon, compared to variant b. The resulting isoform (c) has a shorter and distinct N-terminus, compared to isoform b.

Source sequence(s)

AC106878

Consensus CDS

CCDS75208.1

UniProtKB/TrEMBL

A0A087WU31, B3KXK0, E9PE15

Related

ENSP00000425323.2, ENST00000507875.6

Conserved Domains (2) summary

cd03684
Location:109 → 615

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

cd04591
Location:626 → 776

CBS_pair_voltage-gated_CLC_euk_bac; Two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the voltage gated CLC (chloride channel) in eukaryotes and bacteria
NM_001829.4 → NP_001820.2 H(+)/Cl(-) exchange transporter 3 isoform b

See identical proteins and their annotated locations for NP_001820.2

Status: REVIEWED

Description

Transcript Variant: This variant (b) represents the predominant transcript and encodes isoform b.

Source sequence(s)

AA780395, AC106878, BC136510, BX647119

Consensus CDS

CCDS34101.1

UniProtKB/Swiss-Prot

B7Z932, B9EGJ9, D3DP34, E9PB97, O14918, P51790, Q86Z21

UniProtKB/TrEMBL

B3KXK0

Related

ENSP00000424603.1, ENST00000513761.6

Conserved Domains (2) summary

cd03684
Location:136 → 642

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

cd04591
Location:653 → 803

CBS_pair_voltage-gated_CLC_euk_bac; Two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the voltage gated CLC (chloride channel) in eukaryotes and bacteria
NM_173872.4 → NP_776297.2 H(+)/Cl(-) exchange transporter 3 isoform e

See identical proteins and their annotated locations for NP_776297.2

Status: REVIEWED

Description

Transcript Variant: This variant (e) has an additional exon in the 3' coding region, which results in frame-shift, compared to variant b. The resulting isoform (e) has a longer and distinct C-terminus, compared to isoform b.

Source sequence(s)

AA780395, AB019542, AC106878, AK304362, DA102505

Consensus CDS

CCDS34100.1

UniProtKB/TrEMBL

B3KXK0

Related

ENSP00000261514.5, ENST00000347613.9

Conserved Domains (2) summary

cd03684
Location:136 → 642

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

cd04591
Location:653 → 803

CBS_pair_voltage-gated_CLC_euk_bac; Two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the voltage gated CLC (chloride channel) in eukaryotes and bacteria

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000004.12 Reference GRCh38.p14 Primary Assembly

Range

169620578..169723673

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_047449584.1 → XP_047305540.1 H(+)/Cl(-) exchange transporter 3 isoform X3

UniProtKB/TrEMBL

B3KXK0

Conserved Domains (2) summary

cd03684
Location:78 → 584

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

cd04591
Location:595 → 745

CBS_pair_voltage-gated_CLC_euk_bac; Two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the voltage gated CLC (chloride channel) in eukaryotes and bacteria
XM_005262726.4 → XP_005262783.1 H(+)/Cl(-) exchange transporter 3 isoform X1

UniProtKB/TrEMBL

B3KXK0

Conserved Domains (4) summary

COG0517
Location:629 → 774

CBS; CBS domain [Signal transduction mechanisms]

cd03684
Location:109 → 615

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

cd04591
Location:638 → 776

CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...

pfam00654
Location:194 → 595

Voltage_CLC; Voltage gated chloride channel
XM_047449586.1 → XP_047305542.1 H(+)/Cl(-) exchange transporter 3 isoform X4

UniProtKB/TrEMBL

B3KXK0
XM_011531586.3 → XP_011529888.1 H(+)/Cl(-) exchange transporter 3 isoform X2

UniProtKB/TrEMBL

B3KXK0

Conserved Domains (4) summary

COG0517
Location:621 → 766

CBS; CBS domain [Signal transduction mechanisms]

cd03684
Location:101 → 607

ClC_3_like; ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has ...

cd04591
Location:630 → 768

CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...

pfam00654
Location:186 → 587

Voltage_CLC; Voltage gated chloride channel
XM_047449585.1 → XP_047305541.1 H(+)/Cl(-) exchange transporter 3 isoform X4

UniProtKB/TrEMBL

B3KXK0

Alternate T2T-CHM13v2.0

Genomic

NC_060928.1 Alternate T2T-CHM13v2.0

Range

172980359..173083792

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054348875.1 → XP_054204850.1 H(+)/Cl(-) exchange transporter 3 isoform X5

UniProtKB/TrEMBL

B3KXK0
XM_054348878.1 → XP_054204853.1 H(+)/Cl(-) exchange transporter 3 isoform X6

UniProtKB/Swiss-Prot

B7Z932, B9EGJ9, D3DP34, E9PB97, O14918, P51790, Q86Z21

UniProtKB/TrEMBL

B3KXK0
XM_054348879.1 → XP_054204854.1 H(+)/Cl(-) exchange transporter 3 isoform X3

UniProtKB/TrEMBL

B3KXK0
XM_054348876.1 → XP_054204851.1 H(+)/Cl(-) exchange transporter 3 isoform X1

UniProtKB/TrEMBL

B3KXK0
XM_054348880.1 → XP_054204855.1 H(+)/Cl(-) exchange transporter 3 isoform X4

UniProtKB/TrEMBL

B3KXK0
XM_054348877.1 → XP_054204852.1 H(+)/Cl(-) exchange transporter 3 isoform X2

UniProtKB/TrEMBL

B3KXK0