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NM_203447.4(DOCK8):c.4019A>G (p.Tyr1340Cys) AND Combined immunodeficiency due to DOCK8 deficiency

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Mar 30, 2021
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000645180.20

Allele description [Variation Report for NM_203447.4(DOCK8):c.4019A>G (p.Tyr1340Cys)]

NM_203447.4(DOCK8):c.4019A>G (p.Tyr1340Cys)

Gene:
DOCK8:dedicator of cytokinesis 8 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9p24.3
Genomic location:
Preferred name:
NM_203447.4(DOCK8):c.4019A>G (p.Tyr1340Cys)
HGVS:
  • NC_000009.12:g.420579A>G
  • NG_017007.1:g.210715A>G
  • NM_001190458.2:c.3719A>G
  • NM_001193536.2:c.3815A>G
  • NM_203447.4:c.4019A>GMANE SELECT
  • NP_001177387.1:p.Tyr1240Cys
  • NP_001180465.1:p.Tyr1272Cys
  • NP_001180465.1:p.Tyr1272Cys
  • NP_982272.2:p.Tyr1340Cys
  • NP_982272.2:p.Tyr1340Cys
  • LRG_196t1:c.4019A>G
  • LRG_196:g.210715A>G
  • LRG_196p1:p.Tyr1340Cys
  • NC_000009.11:g.420579A>G
  • NM_001193536.1:c.3815A>G
  • NM_203447.3:c.4019A>G
Protein change:
Y1240C
Links:
dbSNP: rs116920018
NCBI 1000 Genomes Browser:
rs116920018
Molecular consequence:
  • NM_001190458.2:c.3719A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001193536.2:c.3815A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_203447.4:c.4019A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Combined immunodeficiency due to DOCK8 deficiency (HIES2)
Synonyms:
HIES autosomal recessive; Hyper-IgE recurrent infection syndrome, autosomal recessive; HYPER-IgE RECURRENT INFECTION SYNDROME 2, AUTOSOMAL RECESSIVE; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009478; MedGen: C4722305; Orphanet: 217390; OMIM: 243700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000898652Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Mar 30, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001331214Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Benign
(Apr 27, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Homozygous deletion and reduced expression of the DOCK8 gene in human lung cancer.

Takahashi K, Kohno T, Ajima R, Sasaki H, Minna JD, Fujiwara T, Tanaka N, Yokota J.

Int J Oncol. 2006 Feb;28(2):321-8.

PubMed [citation]
PMID:
16391785

Details of each submission

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV000898652.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

DOCK8 NM_203447.3 exon 31 p.Tyr1340Cys (c.4019A>G):This variant has not been reported in the literature but is present in 0.6% (175/25788) of European (Finnish) alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs116920018). This variant is present in ClinVar (Variation ID:372357). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV001331214.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024