VCV000225239.7 - ClinVar

NM_001163435.3(TBCK):c.2060-2A>G

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001163435.3(TBCK):c.2060-2A>G

Variation ID: 225239 Accession: VCV000225239.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q24 4: 106171272 (GRCh38) [ NCBI UCSC ] 4: 107092429 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 21, 2016	Feb 14, 2024	Nov 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001163435.3:c.2060-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001163436.4:c.2060-2A>G		splice acceptor
NM_001163437.3:c.1943-2A>G		splice acceptor
NM_001290768.2:c.1544-2A>G		splice acceptor
NM_033115.5:c.1871-2A>G		splice acceptor
NC_000004.12:g.106171272T>C
NC_000004.11:g.107092429T>C
NG_034057.3:g.150412A>G
LRG_836:g.150412A>G
LRG_836t1:c.2060-2A>G

... more HGVS ... less HGVS

Protein change

Other names

2060-2A-G

Canonical SPDI

NC_000004.12:106171271:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

The Genome Aggregation Database (gnomAD) 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA358274 OMIM: 616899.0006 dbSNP: rs62321379 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TBCK		-	-	GRCh38 GRCh37	812	832

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	Likely pathogenic (3)	criteria provided, single submitter	-	RCV000210871.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 11, 2023	RCV001853381.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	TIDEX, University of British Columbia Accession: SCV000586847.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Sex: female
Pathogenic (Jul 22, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002552600.2 First in ClinVar: Jul 29, 2022 Last updated: Mar 04, 2023	Comment: Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant … (more) Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30542205, 27040691) (less)
Pathogenic (Nov 11, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002228033.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 16199547‚ 27040692‚ 30103036‚ 27040691‚ 30542205 Comment: This sequence change affects an acceptor splice site in intron 22 of the TBCK gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects an acceptor splice site in intron 22 of the TBCK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TBCK are known to be pathogenic (PMID: 27040692, 30103036). This variant is present in population databases (rs62321379, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with TBCK-related conditions (PMID: 27040691, 30542205). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225239). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 19, 2016)	no assertion criteria provided Method: literature only	HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION AND CHARACTERISTIC FACIES 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000267186.2 First in ClinVar: Apr 22, 2016 Last updated: May 21, 2016	Publications: PubMed (1) PubMed: 27040691 Comment on evidence: In 2 sisters of mixed European descent with infantile hypotonia with psychomotor retardation and characteristic facies-3 (IHPRF3; 616900), Bhoj et al. (2016) identified compound heterozygous … (more) In 2 sisters of mixed European descent with infantile hypotonia with psychomotor retardation and characteristic facies-3 (IHPRF3; 616900), Bhoj et al. (2016) identified compound heterozygous mutations in the TBCK gene: a c.2060-2A-G transition (c.2060-2A-G, NM_001163435.2), resulting in a splice site defect and a frameshift, and a 4-bp deletion (c.803_806delTGAA; 616899.0007), resulting in a frameshift and premature termination (Met268ArgfsTer26). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered through the dbSNP, 1000 Genomes Project, and Exome Variant Server databases, and segregated with the disorder in the family. Functional studies and studies of patient cells were not performed. (less)
Likely pathogenic (Jun 20, 2016)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV000599271.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016

Comment:

This sequence change affects an acceptor splice site in intron 22 of the TBCK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TBCK are known to be pathogenic (PMID: 27040692, 30103036). This variant is present in population databases (rs62321379, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with TBCK-related conditions (PMID: 27040691, 30542205). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225239). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Atypical cerebral palsy: genomics analysis enables precision medicine.	Matthews AM	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30542205
Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3.	Zapata-Aldana E	European journal of medical genetics	2019	PMID: 30103036
Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy.	Chong JX	American journal of human genetics	2016	PMID: 27040692
Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia.	Bhoj EJ	American journal of human genetics	2016	PMID: 27040691
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs62321379 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001163435.3(TBCK):c.2060-2A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62321379 ...