9-271638-C-T

Position:

chr9-271638-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.65C>T(p.Ala22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,540,820 control chromosomes in the GnomAD database, including 91,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8186 hom., cov: 32)

Exomes 𝑓: 0.34 ( 83589 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 1.67

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:

ENSG00000235880 (HGNC:):

ENSG00000235880 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=0.004078895).

BP6

Variant 9-271638-C-T is Benign according to our data. Variant chr9-271638-C-T is described in ClinVar as [Benign]. Clinvar id is 137155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-271638-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.65C>T	p.Ala22Val	missense_variant	2/48	ENST00000432829.7	NP_982272.2	Q8NF50-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 link	c.65C>T	p.Ala22Val	missense_variant	2/48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49246

AN:

151900

Hom.:

8189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.277

Gnomad FIN

AF:

0.394

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.352

Gnomad OTH

AF:

0.318

GnomAD3 exomes

AF:

0.328

AC:

51127

AN:

155658

Hom.:

8694

AF XY:

0.328

AC XY:

27025

AN XY:

82318

show subpopulations

Gnomad AFR exome

AF:

0.280

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.260

Gnomad EAS exome

AF:

0.384

Gnomad SAS exome

AF:

0.292

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.349

Gnomad OTH exome

AF:

0.317

GnomAD4 exome

AF:

0.343

AC:

476604

AN:

1388802

Hom.:

83589

Cov.:

AF XY:

0.342

AC XY:

234521

AN XY:

685448

show subpopulations

Gnomad4 AFR exome

AF:

0.274

Gnomad4 AMR exome

AF:

0.278

Gnomad4 ASJ exome

AF:

0.264

Gnomad4 EAS exome

AF:

0.371

Gnomad4 SAS exome

AF:

0.293

Gnomad4 FIN exome

AF:

0.399

Gnomad4 NFE exome

AF:

0.350

Gnomad4 OTH exome

AF:

0.331

GnomAD4 genome

AF:

0.324

AC:

49268

AN:

152018

Hom.:

8186

Cov.:

AF XY:

0.325

AC XY:

24119

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.281

Gnomad4 AMR

AF:

0.276

Gnomad4 ASJ

AF:

0.248

Gnomad4 EAS

AF:

0.405

Gnomad4 SAS

AF:

0.278

Gnomad4 FIN

AF:

0.394

Gnomad4 NFE

AF:

0.352

Gnomad4 OTH

AF:

0.313

Alfa

AF:

0.324

Hom.:

3664

Bravo

AF:

0.316

TwinsUK

AF:

0.347

AC:

1288

ALSPAC

AF:

0.362

AC:

1397

ESP6500AA

AF:

0.293

AC:

405

ESP6500EA

AF:

0.330

AC:

1051

ExAC

AF:

0.309

AC:

7648

Asia WGS

AF:

0.308

AC:

1067

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala22Val in exon 2 of DOCK8: This variant is not expected to have clinical signi ficance because it has been identified in 33.0% (1051/3182) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs506121). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Combined immunodeficiency due to DOCK8 deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Aug 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
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

0.30

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.63

Sift4G

Uncertain

0.0040

Polyphen

0.0010

Vest4

0.060

ClinPred

0.016

GERP RS

4.0

Varity_R

0.10

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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