rs10814431

Variant names:

• chr9-377111-G-C
• rs10814431
• NM_203447.4:c.2340G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.2340G>C​(p.Leu780Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,610,908 control chromosomes in the GnomAD database, including 49,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4817 hom., cov: 33)
  • Exomes 𝑓: 0.24 (44844 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.298
• Publications: 13 publications found

Genes affected

DOCK8 (HGNC:19191): (dedicator of cytokinesis 8) This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jun 2010]

DOCK8 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 9-377111-G-C is Benign according to our data. Variant chr9-377111-G-C is described in ClinVar as Benign. ClinVar VariationId is 137139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.298 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.2340G>C	p.Leu780Leu	synonymous_variant	Exon 20 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.2340G>C	p.Leu780Leu	synonymous_variant	Exon 20 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37504 AN: 152070 Hom.: 4812 Cov.: 33

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.0733

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.225 AC: 55806 AN: 247598 AF XY: 0.229

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.0639

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.245 AC: 356785 AN: 1458722 Hom.: 44844 Cov.: 36 AF XY: 0.245 AC XY: 178104 AN XY: 725640

African (AFR) AF: 0.281 AC: 9387 AN: 33460

American (AMR) AF: 0.205 AC: 9172 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5359 AN: 26136

East Asian (EAS) AF: 0.0778 AC: 3086 AN: 39684

South Asian (SAS) AF: 0.262 AC: 22535 AN: 86176

European-Finnish (FIN) AF: 0.184 AC: 9375 AN: 50874

Middle Eastern (MID) AF: 0.286 AC: 1629 AN: 5704

European-Non Finnish (NFE) AF: 0.253 AC: 281388 AN: 1111684

Other (OTH) AF: 0.246 AC: 14854 AN: 60348

GnomAD4 genome AF: 0.247 AC: 37522 AN: 152186 Hom.: 4817 Cov.: 33 AF XY: 0.241 AC XY: 17954 AN XY: 74410

African (AFR) AF: 0.284 AC: 11786 AN: 41496

American (AMR) AF: 0.234 AC: 3574 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3472

East Asian (EAS) AF: 0.0734 AC: 381 AN: 5188

South Asian (SAS) AF: 0.259 AC: 1252 AN: 4828

European-Finnish (FIN) AF: 0.181 AC: 1919 AN: 10596

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 17015 AN: 68000

Other (OTH) AF: 0.253 AC: 533 AN: 2106

Alfa AF: 0.243 Hom.: 940

Bravo AF: 0.250

Asia WGS AF: 0.164 AC: 571 AN: 3478

EpiCase AF: 0.251

EpiControl AF: 0.259

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu780Leu in exon 20 of DOCK8: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 28.8% (1271/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10814431). -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	3.3
DANN	Benign	0.74
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10814431; hg19: chr9-377111; COSMIC: COSV66618101;