rs17673268

Positions:

chr9-368128-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203447.4(DOCK8):c.1790C>T(p.Ala597Val) variant causes a missense change. The variant allele was found at a frequency of 0.0986 in 1,612,634 control chromosomes in the GnomAD database, including 9,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 609 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8640 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.07

Variant links:

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 links:

DOCK8 (HGNC:):

DOCK8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019554198).

BP6

Variant 9-368128-C-T is Benign according to our data. Variant chr9-368128-C-T is described in ClinVar as [Benign]. Clinvar id is 137136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-368128-C-T is described in Lovd as [Benign]. Variant chr9-368128-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.1790C>T	p.Ala597Val	missense_variant	15/48	ENST00000432829.7	NP_982272.2	Q8NF50-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.1790C>T	p.Ala597Val	missense_variant	15/48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.0752

AC:

11436

AN:

152094

Hom.:

609

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.0923

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0764

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.0703

GnomAD3 exomes

AF:

0.0766

AC:

19260

AN:

251338

Hom.:

1053

AF XY:

0.0760

AC XY:

10317

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0181

Gnomad AMR exome

AF:

0.0355

Gnomad ASJ exome

AF:

0.0794

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0200

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.0780

GnomAD4 exome

AF:

0.101

AC:

147595

AN:

1460422

Hom.:

8640

Cov.:

AF XY:

0.0985

AC XY:

71587

AN XY:

726650

show subpopulations

Gnomad4 AFR exome

AF:

0.0160

Gnomad4 AMR exome

AF:

0.0375

Gnomad4 ASJ exome

AF:

0.0827

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0202

Gnomad4 FIN exome

AF:

0.147

Gnomad4 NFE exome

AF:

0.116

Gnomad4 OTH exome

AF:

0.0824

GnomAD4 genome

AF:

0.0751

AC:

11434

AN:

152212

Hom.:

609

Cov.:

AF XY:

0.0750

AC XY:

5580

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0199

Gnomad4 AMR

AF:

0.0492

Gnomad4 ASJ

AF:

0.0764

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.0162

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.0695

Alfa

AF:

0.0969

Hom.:

2057

Bravo

AF:

0.0657

TwinsUK

AF:

0.108

AC:

399

ALSPAC

AF:

0.114

AC:

441

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.106

AC:

912

ExAC

AF:

0.0751

AC:

9121

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0965

EpiControl

AF:

0.0951

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala597Val in exon 15 of DOCK8: This variant is not expected to have clinical sig nificance because it has been identified in 10.6% (912/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs17673268). -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Autosomal recessive hyper-IgE syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;.;.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;T

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.7

M;.;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.3

.;.;D;N

REVEL

Benign

0.21

Sift

Uncertain

0.0030

.;.;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.35

MPC

0.17

ClinPred

0.029

GERP RS

5.2

Varity_R

0.60

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over