rs34908836

chr9-449874-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):c.5908G>C(p.Ala1970Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,613,720 control chromosomes in the GnomAD database, including 3,600 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1970G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.073 (546 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3054 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.62

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001698941).
• BP6: Variant 9-449874-G-C is Benign according to our data. Variant chr9-449874-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 137154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-449874-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.5908G>C	p.Ala1970Pro	missense_variant	45/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.5908G>C	p.Ala1970Pro	missense_variant	45/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.0725 AC: 11023 AN: 152122 Hom.: 544 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0417

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.0612 AC: 15389 AN: 251416 Hom.: 801 AF XY: 0.0658 AC XY: 8942 AN XY: 135884

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.0478

Gnomad EAS exome AF: 0.0101

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.0455

Gnomad NFE exome AF: 0.0452

Gnomad OTH exome AF: 0.0561

GnomAD4 exome AF: 0.0531 AC: 77552 AN: 1461480 Hom.: 3054 Cov.: 33 AF XY: 0.0563 AC XY: 40938 AN XY: 727014

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.0317

Gnomad4 ASJ exome AF: 0.0491

Gnomad4 EAS exome AF: 0.00625

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.0432

Gnomad4 NFE exome AF: 0.0450

Gnomad4 OTH exome AF: 0.0559

GnomAD4 genome AF: 0.0726 AC: 11052 AN: 152240 Hom.: 546 Cov.: 32 AF XY: 0.0746 AC XY: 5553 AN XY: 74444

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.0516

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.00869

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.0417

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0553

Alfa AF: 0.0498 Hom.: 169

Bravo AF: 0.0713

TwinsUK AF: 0.0423 AC: 157

ALSPAC AF: 0.0397 AC: 153

ESP6500AA AF: 0.133 AC: 584

ESP6500EA AF: 0.0456 AC: 392

ExAC AF: 0.0646 AC: 7842

Asia WGS AF: 0.0930 AC: 324 AN: 3478

EpiCase AF: 0.0529

EpiControl AF: 0.0491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala1970Pro in exon 45 of DOCK8: This variant is not expected to have clinical si gnificance because it has been identified in 13.3% (584/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs34908836). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2014	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. -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	18
Dann	Benign	0.90
DEOGEN2	Benign	0.070	T;.;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.64	T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N;.;.;.
MutationTaster	Benign	0.0037	P;P;P;P
PrimateAI	Uncertain	0.53	T
REVEL	Benign	0.13
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.096
MPC		0.054
ClinPred		0.0076	T
GERP RS		3.7
Varity_R		0.23
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs34908836; hg19: chr9-449874; COSMIC: COSV66620191; COSMIC: COSV66620191;