Variant chr9-432330-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_203447.4(DOCK8):c.4785+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,613,316 control chromosomes in the GnomAD database, including 466,623 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 38123 hom., cov: 30)

Exomes 𝑓: 0.76 ( 428500 hom. )

Consequence

DOCK8
NM_203447.4 splice_region, intron

Scores

Splicing: ADA: 0.00009776

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.213

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 9-432330-C-G is Benign according to our data. Variant chr9-432330-C-G is described in ClinVar as [Benign]. Clinvar id is 163176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-432330-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.4785+6C>G		splice_region_variant, intron_variant	Intron 37 of 47	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.4785+6C>G		splice_region_variant, intron_variant	Intron 37 of 47	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.696

AC:

105596

AN:

151788

Hom.:

38106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.487

Gnomad AMI

AF:

0.638

Gnomad AMR

AF:

0.793

Gnomad ASJ

AF:

0.732

Gnomad EAS

AF:

0.981

Gnomad SAS

AF:

0.689

Gnomad FIN

AF:

0.788

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.763

Gnomad OTH

AF:

0.711

GnomAD3 exomes

AF:

0.766

AC:

192546

AN:

251346

Hom.:

75318

AF XY:

0.763

AC XY:

103642

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.481

Gnomad AMR exome

AF:

0.852

Gnomad ASJ exome

AF:

0.712

Gnomad EAS exome

AF:

0.985

Gnomad SAS exome

AF:

0.688

Gnomad FIN exome

AF:

0.795

Gnomad NFE exome

AF:

0.766

Gnomad OTH exome

AF:

0.757

GnomAD4 exome

AF:

0.763

AC:

1114842

AN:

1461410

Hom.:

428500

Cov.:

AF XY:

0.761

AC XY:

553218

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.476

Gnomad4 AMR exome

AF:

0.845

Gnomad4 ASJ exome

AF:

0.713

Gnomad4 EAS exome

AF:

0.980

Gnomad4 SAS exome

AF:

0.689

Gnomad4 FIN exome

AF:

0.794

Gnomad4 NFE exome

AF:

0.766

Gnomad4 OTH exome

AF:

0.757

GnomAD4 genome

AF:

0.696

AC:

105662

AN:

151906

Hom.:

38123

Cov.:

AF XY:

0.700

AC XY:

51954

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.487

Gnomad4 AMR

AF:

0.793

Gnomad4 ASJ

AF:

0.732

Gnomad4 EAS

AF:

0.981

Gnomad4 SAS

AF:

0.690

Gnomad4 FIN

AF:

0.788

Gnomad4 NFE

AF:

0.763

Gnomad4 OTH

AF:

0.713

Alfa

AF:

0.730

Hom.:

10715

Bravo

AF:

0.690

Asia WGS

AF:

0.823

AC:

2862

AN:

3478

EpiCase

AF:

0.751

EpiControl

AF:

0.763

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 92. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	4785+6C>G in intron 37 of DOCK8: This variant is not expected to have clinical s ignificance because it has been identified in 49.3% (2171/4406) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs7036567). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2Other: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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Combined immunodeficiency due to DOCK8 deficiency

Benign:2

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 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. -

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.6

DANN

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000098

dbscSNV1_RF

Benign

0.042

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