chr9-449874-G-C

Position:

chr9-449874-G-C

Variant summary

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

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 (★★).

Frequency

Genomes: 𝑓 0.073 ( 546 hom., cov: 32)

Exomes 𝑓: 0.053 ( 3054 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.62

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:

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=0.001698941).

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	Protein	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.5908G>C	p.Ala1970Pro	missense_variant	45/48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.5908G>C	p.Ala1970Pro	missense_variant	45/48	1	NM_203447.4	ENSP00000394888		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.0725

AC:

11023

AN:

152122

Hom.:

544

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0563

AC XY:

40938

AN XY:

727014

show subpopulations

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.:

AF XY:

0.0746

AC XY:

5553

AN XY:

74444

show subpopulations

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.070

T;.;.;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.64

T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.56

N;.;.;.

MutationTaster

Benign

0.0037

P;P;P;P

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.060

.;.;N;N

REVEL

Benign

0.13

Sift

Benign

0.60

.;.;T;T

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.096

MPC

0.054

ClinPred

0.0076

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

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