VCV000137155.26 - ClinVar

NM_203447.4(DOCK8):c.65C>T (p.Ala22Val)

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.

(12)

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.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_203447.4(DOCK8):c.65C>T (p.Ala22Val)

Variation ID: 137155 Accession: VCV000137155.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p24.3 9: 271638 (GRCh38) [ NCBI UCSC ] 9: 271638 (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	Mar 16, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_203447.4:c.65C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_982272.2:p.Ala22Val	missense
NC_000009.12:g.271638C>T
NC_000009.11:g.271638C>T
NG_017007.1:g.61774C>T
LRG_196:g.61774C>T
LRG_196t1:c.65C>T	LRG_196p1:p.Ala22Val

... more HGVS ... less HGVS

Protein change

A22V

Other names

p.A22V:GCG>GTG

Canonical SPDI

NC_000009.12:271637:C:T

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.

0.30771 (T)

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

1000 Genomes Project 30x 0.30387

1000 Genomes Project 0.30771

Trans-Omics for Precision Medicine (TOPMed) 0.31611

Exome Aggregation Consortium (ExAC) 0.32449

The Genome Aggregation Database (gnomAD) 0.32449

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.31888

The Genome Aggregation Database (gnomAD), exomes 0.32846

Links

ClinGen: CA175834 dbSNP: rs506121 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.
DOCK8		-	-	GRCh38 GRCh37	2409	3010

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.
not specified	Benign (6)	criteria provided, multiple submitters, no conflicts	Nov 12, 2023	RCV000150504.23
Combined immunodeficiency due to DOCK8 deficiency	Benign (3)	criteria provided, multiple submitters, no conflicts	Jul 14, 2021	RCV000210052.21
not provided	Benign (2)	criteria provided, single submitter	-	RCV001824623.10
Autosomal recessive hyper-IgE syndrome	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV003761770.2

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.
Benign (Aug 25, 2015)	criteria provided, single submitter (Kienzler et al. (Clin Immunol. 2016)) Method: clinical testing	Combined immunodeficiency due to DOCK8 deficiency Affected status: yes, no Allele origin: maternal, germline	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust Accession: SCV000257462.1 First in ClinVar: Mar 16, 2016 Last updated: Mar 16, 2016	Publications: PubMed (1) PubMed: 26680607 Observation 1: Clinical Features: Recurrent bacterial chest infections (present) , Mild eczema (present) , Asthma (present) , Low serum IgM (present) , Normal IgA and IgE (present) , Borderline-low … (more) Recurrent bacterial chest infections (present) , Mild eczema (present) , Asthma (present) , Low serum IgM (present) , Normal IgA and IgE (present) , Borderline-low IgG levels which dropped significantly over 12 months (present) (less) Observation 2: Family history: no
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000317180.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Mar 11, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000168223.4 First in ClinVar: May 29, 2016 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jul 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined immunodeficiency due to DOCK8 deficiency Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001763314.1 First in ClinVar: Aug 05, 2021 Last updated: Aug 05, 2021	Sex: mixed
Benign (Nov 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan Accession: SCV004102261.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Publications: PubMed (1) PubMed: 25741868 Comment: This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied by a panel of primary … (more) This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported. (less) Number of individuals with the variant: 40 Age: <18 years Sex: mixed
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Combined immunodeficiency due to DOCK8 deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001724050.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005270366.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Feb 21, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000197690.4 First in ClinVar: Jan 31, 2015 Last updated: Oct 02, 2016	Comment: Ala22Val in exon 2 of DOCK8: This variant is not expected to have clinical signi ficance because it has been identified in 33.0% (1051/3182) of … (more) Ala22Val in exon 2 of DOCK8: This variant is not expected to have clinical signi ficance because it has been identified in 33.0% (1051/3182) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs506121). (less) Number of individuals with the variant: 35
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Combined immunodeficiency due to DOCK8 deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000479382.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740934.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927379.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074631.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Comment: Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. (less) Clinical Features: Phenotypic abnormality (present) Indication for testing: Diagnostic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-04-27 Testing laboratory interpretation: Benign
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

Ala22Val in exon 2 of DOCK8: This variant is not expected to have clinical signi ficance because it has been identified in 33.0% (1051/3182) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs506121).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

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
Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency without hyper-IgE.	Kienzler AK	Clinical immunology (Orlando, Fla.)	2016	PMID: 26680607
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868

Text-mined citations for rs506121 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_203447.4(DOCK8):c.65C>T (p.Ala22Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs506121 ...