9-271638-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203447.4(DOCK8):c.65C>T(p.Ala22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,540,820 control chromosomes in the GnomAD database, including 91,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A22A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 8186 hom., cov: 32)

Exomes 𝑓: 0.34 ( 83589 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 1.67

Publications

28 publications found

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 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

DOCK8 links:

ENSG00000235880 (HGNC:):

ENSG00000235880 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.004078895).

BP6

Variant 9-271638-C-T is Benign according to our data. Variant chr9-271638-C-T is described in ClinVar as [Benign]. Clinvar id is 137155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.65C>T	p.Ala22Val	missense_variant	Exon 2 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.65C>T	p.Ala22Val	missense_variant	Exon 2 of 48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49246

AN:

151900

Hom.:

8189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.277

Gnomad FIN

AF:

0.394

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.352

Gnomad OTH

AF:

0.318

GnomAD2 exomes

AF:

0.328

AC:

51127

AN:

155658

AF XY:

0.328

show subpopulations

Gnomad AFR exome

AF:

0.280

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.260

Gnomad EAS exome

AF:

0.384

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.349

Gnomad OTH exome

AF:

0.317

GnomAD4 exome

AF:

0.343

AC:

476604

AN:

1388802

Hom.:

83589

Cov.:

AF XY:

0.342

AC XY:

234521

AN XY:

685448

show subpopulations

African (AFR)

AF:

0.274

AC:

8571

AN:

31326

American (AMR)

AF:

0.278

AC:

9812

AN:

35348

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

6634

AN:

25092

East Asian (EAS)

AF:

0.371

AC:

13196

AN:

35598

South Asian (SAS)

AF:

0.293

AC:

23097

AN:

78762

European-Finnish (FIN)

AF:

0.399

AC:

19597

AN:

49166

Middle Eastern (MID)

AF:

0.289

AC:

1638

AN:

5670

European-Non Finnish (NFE)

AF:

0.350

AC:

374970

AN:

1070114

Other (OTH)

AF:

0.331

AC:

19089

AN:

57726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

14505

29011

43516

58022

72527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.324

AC:

49268

AN:

152018

Hom.:

8186

Cov.:

AF XY:

0.325

AC XY:

24119

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.281

AC:

11661

AN:

41462

American (AMR)

AF:

0.276

AC:

4220

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

860

AN:

3470

East Asian (EAS)

AF:

0.405

AC:

2099

AN:

5188

South Asian (SAS)

AF:

0.278

AC:

1339

AN:

4824

European-Finnish (FIN)

AF:

0.394

AC:

4152

AN:

10530

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.352

AC:

23902

AN:

67964

Other (OTH)

AF:

0.313

AC:

662

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1673

3347

5020

6694

8367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.320

Hom.:

5680

Bravo

AF:

0.316

TwinsUK

AF:

0.347

AC:

1288

ALSPAC

AF:

0.362

AC:

1397

ESP6500AA

AF:

0.293

AC:

405

ESP6500EA

AF:

0.330

AC:

1051

ExAC

AF:

0.309

AC:

7648

Asia WGS

AF:

0.308

AC:

1067

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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. -

Mar 11, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

Ala22Val in exon 2 of DOCK8: This variant is not expected to have clinical signi ficance because it has been identified in 33.0% (1051/3182) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs506121). -

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

- -

Combined immunodeficiency due to DOCK8 deficiency

Benign:3

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 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2015

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.3

PhyloP100

1.7

PrimateAI

Uncertain

0.63

Sift4G

Uncertain

0.0040

Polyphen

0.0010

Vest4

0.060

ClinPred

0.016

GERP RS

4.0

Varity_R

0.10

gMVP

0.50

Mutation Taster

=79/21

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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9-271638-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over