Variant NM_203447.4:c.2340G>C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_203447.4(DOCK8):c.2340G>C(p.Leu780Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,610,908 control chromosomes in the GnomAD database, including 49,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 4817 hom., cov: 33)

Exomes 𝑓: 0.24 ( 44844 hom. )

Consequence

DOCK8
NM_203447.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.298

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 9-377111-G-C is Benign according to our data. Variant chr9-377111-G-C is described in ClinVar as [Benign]. Clinvar id is 137139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-377111-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.298 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.2340G>C	p.Leu780Leu	synonymous_variant	Exon 20 of 48	ENST00000432829.7	NP_982272.2	Q8NF50-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 link	c.2340G>C	p.Leu780Leu	synonymous_variant	Exon 20 of 48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.247

AC:

37504

AN:

152070

Hom.:

4812

Cov.:

show subpopulations

Gnomad AFR

AF:

0.284

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.0733

Gnomad SAS

AF:

0.258

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.256

GnomAD3 exomes

AF:

0.225

AC:

55806

AN:

247598

Hom.:

6724

AF XY:

0.229

AC XY:

30746

AN XY:

134058

show subpopulations

Gnomad AFR exome

AF:

0.284

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.0639

Gnomad SAS exome

AF:

0.263

Gnomad FIN exome

AF:

0.185

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.234

GnomAD4 exome

AF:

0.245

AC:

356785

AN:

1458722

Hom.:

44844

Cov.:

AF XY:

0.245

AC XY:

178104

AN XY:

725640

show subpopulations

Gnomad4 AFR exome

AF:

0.281

Gnomad4 AMR exome

AF:

0.205

Gnomad4 ASJ exome

AF:

0.205

Gnomad4 EAS exome

AF:

0.0778

Gnomad4 SAS exome

AF:

0.262

Gnomad4 FIN exome

AF:

0.184

Gnomad4 NFE exome

AF:

0.253

Gnomad4 OTH exome

AF:

0.246

GnomAD4 genome

AF:

0.247

AC:

37522

AN:

152186

Hom.:

4817

Cov.:

AF XY:

0.241

AC XY:

17954

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.284

Gnomad4 AMR

AF:

0.234

Gnomad4 ASJ

AF:

0.193

Gnomad4 EAS

AF:

0.0734

Gnomad4 SAS

AF:

0.259

Gnomad4 FIN

AF:

0.181

Gnomad4 NFE

AF:

0.250

Gnomad4 OTH

AF:

0.253

Alfa

AF:

0.243

Hom.:

940

Bravo

AF:

0.250

Asia WGS

AF:

0.164

AC:

571

AN:

3478

EpiCase

AF:

0.251

EpiControl

AF:

0.259

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Sep 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu780Leu in exon 20 of DOCK8: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 28.8% (1271/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10814431). -

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Combined immunodeficiency due to DOCK8 deficiency

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

3.3

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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