rs2039045

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_203447.4(DOCK8):c.699T>C(p.Asn233Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,614,032 control chromosomes in the GnomAD database, including 30,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3100 hom., cov: 33)

Exomes 𝑓: 0.19 ( 27038 hom. )

Consequence

DOCK8
NM_203447.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.300

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 9-312124-T-C is Benign according to our data. Variant chr9-312124-T-C is described in ClinVar as [Benign]. Clinvar id is 137157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-312124-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.3 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 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.699T>C	p.Asn233Asn	synonymous_variant	6/48	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.699T>C	p.Asn233Asn	synonymous_variant	6/48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.194

AC:

29500

AN:

152070

Hom.:

3100

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.113

Gnomad EAS

AF:

0.00713

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.151

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.186

GnomAD3 exomes

AF:

0.165

AC:

41407

AN:

251196

Hom.:

3880

AF XY:

0.165

AC XY:

22446

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.126

Gnomad EAS exome

AF:

0.00561

Gnomad SAS exome

AF:

0.156

Gnomad FIN exome

AF:

0.157

Gnomad NFE exome

AF:

0.187

Gnomad OTH exome

AF:

0.165

GnomAD4 exome

AF:

0.187

AC:

274011

AN:

1461844

Hom.:

27038

Cov.:

AF XY:

0.186

AC XY:

135558

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.245

Gnomad4 AMR exome

AF:

0.164

Gnomad4 ASJ exome

AF:

0.126

Gnomad4 EAS exome

AF:

0.00416

Gnomad4 SAS exome

AF:

0.156

Gnomad4 FIN exome

AF:

0.153

Gnomad4 NFE exome

AF:

0.199

Gnomad4 OTH exome

AF:

0.182

GnomAD4 genome

AF:

0.194

AC:

29508

AN:

152188

Hom.:

3100

Cov.:

AF XY:

0.190

AC XY:

14099

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.246

Gnomad4 AMR

AF:

0.182

Gnomad4 ASJ

AF:

0.113

Gnomad4 EAS

AF:

0.00734

Gnomad4 SAS

AF:

0.160

Gnomad4 FIN

AF:

0.151

Gnomad4 NFE

AF:

0.193

Gnomad4 OTH

AF:

0.184

Alfa

AF:

0.170

Hom.:

1215

Bravo

AF:

0.198

Asia WGS

AF:

0.0940

AC:

327

AN:

3478

EpiCase

AF:

0.190

EpiControl

AF:

0.194

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 29% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Asn233Asn in exon 6 of DOCK8: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 25.2% (1110/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2039045). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 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	-	- -

Combined immunodeficiency due to DOCK8 deficiency

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

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

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.8

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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