rs11789099

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.709G>A(p.Glu237Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,614,184 control chromosomes in the GnomAD database, including 905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 73 hom., cov: 33)

Exomes 𝑓: 0.031 ( 832 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.80

Publications

16 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:

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=0.0031790435).

BP6

Variant 9-312134-G-A is Benign according to our data. Variant chr9-312134-G-A is described in ClinVar as Benign. ClinVar VariationId is 163173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.709G>A	p.Glu237Lys	missense_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 link	c.709G>A	p.Glu237Lys	missense_variant	Exon 6 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes

AF:

0.0235

AC:

3571

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00745

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.0251

Gnomad ASJ

AF:

0.0495

Gnomad EAS

AF:

0.000768

Gnomad SAS

AF:

0.0513

Gnomad FIN

AF:

0.0169

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0313

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0283

AC:

7105

AN:

251142

AF XY:

0.0311

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.0530

Gnomad EAS exome

AF:

0.000762

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.0314

Gnomad OTH exome

AF:

0.0330

GnomAD4 exome

AF:

0.0308

AC:

45086

AN:

1461848

Hom.:

832

Cov.:

AF XY:

0.0321

AC XY:

23311

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00636

AC:

213

AN:

33480

American (AMR)

AF:

0.0166

AC:

743

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0515

AC:

1345

AN:

26134

East Asian (EAS)

AF:

0.00108

AC:

AN:

39700

South Asian (SAS)

AF:

0.0559

AC:

4821

AN:

86248

European-Finnish (FIN)

AF:

0.0170

AC:

906

AN:

53420

Middle Eastern (MID)

AF:

0.0404

AC:

233

AN:

5768

European-Non Finnish (NFE)

AF:

0.0315

AC:

35042

AN:

1111982

Other (OTH)

AF:

0.0288

AC:

1740

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2710

5420

8131

10841

13551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1316

2632

3948

5264

6580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0234

AC:

3567

AN:

152336

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1732

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00748

AC:

311

AN:

41572

American (AMR)

AF:

0.0251

AC:

384

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0495

AC:

172

AN:

3472

East Asian (EAS)

AF:

0.000770

AC:

AN:

5194

South Asian (SAS)

AF:

0.0505

AC:

244

AN:

4830

European-Finnish (FIN)

AF:

0.0169

AC:

180

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0313

AC:

2130

AN:

68024

Other (OTH)

AF:

0.0227

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

180

360

541

721

901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0292

Hom.:

317

Bravo

AF:

0.0227

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0343

AC:

132

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0329

AC:

283

ExAC

AF:

0.0287

AC:

3484

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0345

EpiControl

AF:

0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

Glu237Lys in exon 6 of DOCK8: This variant is not expected to have clinical sign ificance because it has been identified in 3.3% (283/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs11789099). -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.2

.;N;N

REVEL

Benign

0.16

Sift

Benign

0.54

.;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

0.78

P;.;.

Vest4

0.28

MPC

0.19

ClinPred

0.014

GERP RS

5.6

Varity_R

0.32

gMVP

0.49

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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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