VCV000253047.18 - ClinVar

NM_020812.4(DOCK6):c.5939+2T>C

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.

(8)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020812.4(DOCK6):c.5939+2T>C

Variation ID: 253047 Accession: VCV000253047.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11200714 (GRCh38) [ NCBI UCSC ] 19: 11311390 (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	Aug 22, 2016	Oct 8, 2024	Oct 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020812.4:c.5939+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001367830.1:c.6044+2T>C		splice donor
NC_000019.10:g.11200714A>G
NC_000019.9:g.11311390A>G
NG_031953.1:g.66779T>C
NG_051186.1:g.1854T>C
NG_051186.2:g.2151T>C

... more HGVS ... less HGVS

Protein change

Other names

IVS46DS, +2, T-C

Canonical SPDI

NC_000019.10:11200713:A:G

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00018

The Genome Aggregation Database (gnomAD) 0.00019

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00025

Exome Aggregation Consortium (ExAC) 0.00042

Links

OMIM: 614194.0006 dbSNP: rs201387914 ClinGen: CA9206295 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.
DOCK6		-	-	GRCh38 GRCh37	933	1340

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.
Adams-Oliver syndrome 2	Pathogenic (2)	criteria provided, single submitter	Apr 5, 2020	RCV000239583.8
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Oct 14, 2023	RCV001242778.11
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jun 2, 2021	RCV002518540.2
DOCK6-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 19, 2024	RCV004751400.1

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.
Pathogenic (Feb 16, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001817220.3 First in ClinVar: Sep 08, 2021 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: 25824905, 30111349, 31654484, 29961505, 29924900, 31589614, 28884918) (less)
Pathogenic (Apr 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adams-Oliver syndrome 2 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021733.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 14, 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: SCV001415887.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 16199547‚ 21820096‚ 25824905‚ 28884918‚ 30111349 Comment: This sequence change affects a donor splice site in intron 46 of the DOCK6 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 46 of the DOCK6 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 DOCK6 are known to be pathogenic (PMID: 21820096, 25824905). This variant is present in population databases (rs201387914, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Aicardi-GoutieÃÄres syndrome and Adams-Oliver syndrome (PMID: 25824905, 28884918, 30111349). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253047). 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 (Jun 02, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003621663.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 28884918‚ 29961505 Comment: The c.5939+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 46 of the DOCK6 gene. Alterations that disrupt the … (more) The c.5939+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 46 of the DOCK6 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the DOCK6 c.5939+2T>C alteration was observed in 0.02% (58/277380) of total alleles studied, with a frequency of 0.04% (46/127132) in the European (non-Finnish) subpopulation. This alteration has been reported in the literature in combination with other DOCK6 mutations in patients with features consistent with Adams-Oliver syndrome (Jones, 2017; Dugan, 2018). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001978647.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980096.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Nov 02, 2023)	no assertion criteria provided Method: literature only	ADAMS-OLIVER SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000297836.2 First in ClinVar: Aug 22, 2016 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 25824905 Comment on evidence: For discussion of the c.5939+2T-C transition (rs201387914) in intron 46 of the DOCK6 gene that was found in compound heterozygous state in a sister and … (more) For discussion of the c.5939+2T-C transition (rs201387914) in intron 46 of the DOCK6 gene that was found in compound heterozygous state in a sister and brother with Adam-Oliver syndrome-2 (AOS2; 614219) by Sukalo et al. (2015), see 614194.0005. (less)
Pathogenic (Jun 19, 2024)	no assertion criteria provided Method: clinical testing	DOCK6-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005351052.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The DOCK6 c.5939+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous … (more) The DOCK6 c.5939+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with Adams-Oliver syndrome, with the phenotype co-segregating in one family (see for example - Sukalo. 2015. PubMed ID: 25824905; Jones et al. 2017. PubMed ID: 28884918; Dudoignon et al. 2020. PubMed ID: 31654484). This variant has also been documented in the compound heterozygous state in an individual who fulfilled the clinical criteria for Aicardi-Goutieres syndrome (Tonduti et al. 2018. PubMed ID: 30111349). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in DOCK6 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

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 is associated with the following publications: (PMID: 25824905, 30111349, 31654484, 29961505, 29924900, 31589614, 28884918)

Comment:

This sequence change affects a donor splice site in intron 46 of the DOCK6 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 DOCK6 are known to be pathogenic (PMID: 21820096, 25824905). This variant is present in population databases (rs201387914, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Aicardi-GoutieÃÄres syndrome and Adams-Oliver syndrome (PMID: 25824905, 28884918, 30111349). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253047). 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.

Comment:

The c.5939+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 46 of the DOCK6 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the DOCK6 c.5939+2T>C alteration was observed in 0.02% (58/277380) of total alleles studied, with a frequency of 0.04% (46/127132) in the European (non-Finnish) subpopulation. This alteration has been reported in the literature in combination with other DOCK6 mutations in patients with features consistent with Adams-Oliver syndrome (Jones, 2017; Dugan, 2018). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The DOCK6 c.5939+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with Adams-Oliver syndrome, with the phenotype co-segregating in one family (see for example - Sukalo. 2015. PubMed ID: 25824905; Jones et al. 2017. PubMed ID: 28884918; Dudoignon et al. 2020. PubMed ID: 31654484). This variant has also been documented in the compound heterozygous state in an individual who fulfilled the clinical criteria for Aicardi-Goutieres syndrome (Tonduti et al. 2018. PubMed ID: 30111349). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in DOCK6 are expected to be pathogenic. This variant is interpreted 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
Encephalopathies with intracranial calcification in children: clinical and genetic characterization.	Tonduti D	Orphanet journal of rare diseases	2018	PMID: 30111349
Intracranial Calcifications in Young Children.	Dugan SL	Seminars in pediatric neurology	2018	PMID: 29961505
Adams-Oliver Syndrome Type 2 in Association with Compound Heterozygous DOCK6 Mutations.	Jones KM	Pediatric dermatology	2017	PMID: 28884918
DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.	Sukalo M	Human mutation	2015	PMID: 25824905
Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome.	Shaheen R	American journal of human genetics	2011	PMID: 21820096
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs201387914 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_020812.4(DOCK6):c.5939+2T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201387914 ...