9-328006-T-C

Variant names:

• chr9-328006-T-C
• rs2296828
• NM_203447.4:c.895-16T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.895-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 1,610,546 control chromosomes in the GnomAD database, including 377,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34415 hom., cov: 33)
  • Exomes 𝑓: 0.69 (343321 hom.)
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.38
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 9-328006-T-C is Benign according to our data. Variant chr9-328006-T-C is described in ClinVar as Benign. ClinVar VariationId is 263271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.895-16T>C		intron_variant	Intron 8 of 47	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.895-16T>C		intron_variant	Intron 8 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.671 AC: 102042 AN: 151980 Hom.: 34403 Cov.: 33

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.655

GnomAD2 exomes AF: 0.688 AC: 172761 AN: 251148 AF XY: 0.692

Gnomad AFR exome AF: 0.658

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.726

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.672

GnomAD4 exome AF: 0.685 AC: 999366 AN: 1458448 Hom.: 343321 Cov.: 34 AF XY: 0.688 AC XY: 499504 AN XY: 725798

African (AFR) AF: 0.651 AC: 21724 AN: 33394

American (AMR) AF: 0.680 AC: 30405 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 14976 AN: 26116

East Asian (EAS) AF: 0.719 AC: 28512 AN: 39678

South Asian (SAS) AF: 0.766 AC: 65951 AN: 86148

European-Finnish (FIN) AF: 0.671 AC: 35798 AN: 53360

Middle Eastern (MID) AF: 0.656 AC: 3764 AN: 5736

European-Non Finnish (NFE) AF: 0.683 AC: 757917 AN: 1109034

Other (OTH) AF: 0.669 AC: 40319 AN: 60272

GnomAD4 genome AF: 0.671 AC: 102099 AN: 152098 Hom.: 34415 Cov.: 33 AF XY: 0.671 AC XY: 49921 AN XY: 74364

African (AFR) AF: 0.654 AC: 27123 AN: 41468

American (AMR) AF: 0.668 AC: 10212 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1974 AN: 3466

East Asian (EAS) AF: 0.714 AC: 3693 AN: 5172

South Asian (SAS) AF: 0.768 AC: 3707 AN: 4826

European-Finnish (FIN) AF: 0.660 AC: 6975 AN: 10572

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.679 AC: 46138 AN: 67988

Other (OTH) AF: 0.660 AC: 1393 AN: 2112

Alfa AF: 0.659 Hom.: 7645

Bravo AF: 0.669

Asia WGS AF: 0.751 AC: 2611 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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 90% of patients studied by a panel of primary immunodeficiencies. Number of patients: 86. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

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

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical 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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.71
CADD	Benign	8.1
DANN	Benign	0.83
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2296828; hg19: chr9-328006; COSMIC: COSV66634158;