9-368128-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.1790C>T(p.Ala597Val) variant causes a missense change. The variant allele was found at a frequency of 0.0986 in 1,612,634 control chromosomes in the GnomAD database, including 9,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A597G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.075 ( 609 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8640 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.07

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:

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=0.0019554198).

BP6

Variant 9-368128-C-T is Benign according to our data. Variant chr9-368128-C-T is described in ClinVar as Benign. ClinVar VariationId is 137136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.1790C>T	p.Ala597Val	missense_variant	Exon 15 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.1790C>T	p.Ala597Val	missense_variant	Exon 15 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes

AF:

0.0752

AC:

11436

AN:

152094

Hom.:

609

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.0923

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0764

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.0703

GnomAD2 exomes

AF:

0.0766

AC:

19260

AN:

251338

AF XY:

0.0760

show subpopulations

Gnomad AFR exome

AF:

0.0181

Gnomad AMR exome

AF:

0.0355

Gnomad ASJ exome

AF:

0.0794

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.0780

GnomAD4 exome

AF:

0.101

AC:

147595

AN:

1460422

Hom.:

8640

Cov.:

AF XY:

0.0985

AC XY:

71587

AN XY:

726650

show subpopulations

African (AFR)

AF:

0.0160

AC:

537

AN:

33464

American (AMR)

AF:

0.0375

AC:

1677

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0827

AC:

2161

AN:

26130

East Asian (EAS)

AF:

0.000227

AC:

AN:

39694

South Asian (SAS)

AF:

0.0202

AC:

1743

AN:

86250

European-Finnish (FIN)

AF:

0.147

AC:

7850

AN:

53416

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5768

European-Non Finnish (NFE)

AF:

0.116

AC:

128537

AN:

1110608

Other (OTH)

AF:

0.0824

AC:

4975

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

6333

12665

18998

25330

31663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4532

9064

13596

18128

22660

<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:

0.0751

AC:

11434

AN:

152212

Hom.:

609

Cov.:

AF XY:

0.0750

AC XY:

5580

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0199

AC:

828

AN:

41552

American (AMR)

AF:

0.0492

AC:

752

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0764

AC:

265

AN:

3468

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.0162

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.144

AC:

1519

AN:

10584

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7751

AN:

68000

Other (OTH)

AF:

0.0695

AC:

147

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

519

1038

1558

2077

2596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.0950

Hom.:

3687

Bravo

AF:

0.0657

TwinsUK

AF:

0.108

AC:

399

ALSPAC

AF:

0.114

AC:

441

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.106

AC:

912

ExAC

AF:

0.0751

AC:

9121

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0965

EpiControl

AF:

0.0951

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 07, 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

Ala597Val in exon 15 of DOCK8: This variant is not expected to have clinical sig nificance because it has been identified in 10.6% (912/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs17673268). -

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. -

not provided

Benign:1

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

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;.;.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;T

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.7

M;.;.;.

PhyloP100

6.1

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.3

.;.;D;N

REVEL

Benign

0.21

Sift

Uncertain

0.0030

.;.;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.35

MPC

0.17

ClinPred

0.029

GERP RS

5.2

Varity_R

0.60

gMVP

0.31

Mutation Taster

=243/57

polymorphism (auto)

(source)

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

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