rs2039045

Variant names:

• chr9-312124-T-C
• rs2039045
• NM_203447.4:c.699T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-312124-T-C
• chr9-312124-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.300
• Publications: 7 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 -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 VariationId is 137157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.699T>C	p.Asn233Asn	synonymous_variant	Exon 6 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.699T>C	p.Asn233Asn	synonymous_variant	Exon 6 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29500 AN: 152070 Hom.: 3100 Cov.: 33

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

GnomAD2 exomes AF: 0.165 AC: 41407 AN: 251196 AF XY: 0.165

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 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.: 33 AF XY: 0.186 AC XY: 135558 AN XY: 727224

African (AFR) AF: 0.245 AC: 8201 AN: 33480

American (AMR) AF: 0.164 AC: 7343 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3302 AN: 26136

East Asian (EAS) AF: 0.00416 AC: 165 AN: 39700

South Asian (SAS) AF: 0.156 AC: 13423 AN: 86258

European-Finnish (FIN) AF: 0.153 AC: 8191 AN: 53414

Middle Eastern (MID) AF: 0.194 AC: 1120 AN: 5766

European-Non Finnish (NFE) AF: 0.199 AC: 221280 AN: 1111970

Other (OTH) AF: 0.182 AC: 10986 AN: 60396

GnomAD4 genome AF: 0.194 AC: 29508 AN: 152188 Hom.: 3100 Cov.: 33 AF XY: 0.190 AC XY: 14099 AN XY: 74398

African (AFR) AF: 0.246 AC: 10203 AN: 41512

American (AMR) AF: 0.182 AC: 2781 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 394 AN: 3472

East Asian (EAS) AF: 0.00734 AC: 38 AN: 5176

South Asian (SAS) AF: 0.160 AC: 770 AN: 4822

European-Finnish (FIN) AF: 0.151 AC: 1601 AN: 10600

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13134 AN: 67998

Other (OTH) AF: 0.184 AC: 388 AN: 2106

Alfa AF: 0.173 Hom.: 1558

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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 29% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -

Mar 20, 2014

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. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Combined immunodeficiency due to DOCK8 deficiency Benign:2

Jan 12, 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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other: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

- -

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	-0.53
CADD	Benign	5.8
DANN	Benign	0.48
PhyloP100		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2039045; hg19: chr9-312124; COSMIC: COSV66634218;