rs10491684

Variant names:

• chr9-449798-G-A
• rs10491684
• NM_203447.4:c.5832G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-449798-G-A
• chr9-449798-G-C
• chr9-449798-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.5832G>A​(p.Pro1944Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,612,724 control chromosomes in the GnomAD database, including 4,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (748 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3883 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.905

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 9-449798-G-A is Benign according to our data. Variant chr9-449798-G-A is described in ClinVar as [Benign]. Clinvar id is 137153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.905 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5832G>A	p.Pro1944Pro	synonymous_variant	Exon 45 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.5832G>A	p.Pro1944Pro	synonymous_variant	Exon 45 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.0900 AC: 13675 AN: 151982 Hom.: 744 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0295

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0729

Gnomad OTH AF: 0.0999

GnomAD3 exomes AF: 0.0673 AC: 16929 AN: 251396 Hom.: 719 AF XY: 0.0665 AC XY: 9038 AN XY: 135866

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0449

Gnomad ASJ exome AF: 0.0924

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0403

Gnomad FIN exome AF: 0.0860

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0699 AC: 102065 AN: 1460624 Hom.: 3883 Cov.: 32 AF XY: 0.0695 AC XY: 50471 AN XY: 726642

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0478

Gnomad4 ASJ exome AF: 0.0922

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.0854

Gnomad4 NFE exome AF: 0.0716

Gnomad4 OTH exome AF: 0.0709

GnomAD4 genome AF: 0.0900 AC: 13686 AN: 152100 Hom.: 748 Cov.: 32 AF XY: 0.0869 AC XY: 6459 AN XY: 74364

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.0566

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0297

Gnomad4 FIN AF: 0.0844

Gnomad4 NFE AF: 0.0729

Gnomad4 OTH AF: 0.0993

Alfa AF: 0.0768 Hom.: 775

Bravo AF: 0.0914

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0750

EpiControl AF: 0.0758

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 11, 2014

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. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro1944Pro in exon 45 of DOCK8: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 15.4% (677/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10491684). -

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.69
CADD	Benign	6.3
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs10491684; hg19: chr9-449798; COSMIC: COSV66619896; COSMIC: COSV66619896;