chr9-286593-C-A

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.289C>A(p.Pro97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 1,613,234 control chromosomes in the GnomAD database, including 204,070 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. P97A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.48 ( 18265 hom., cov: 32)

Exomes 𝑓: 0.50 ( 185805 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.24

Publications

50 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=3.5923292E-6).

BP6

Variant 9-286593-C-A is Benign according to our data. Variant chr9-286593-C-A is described in ClinVar as Benign. ClinVar VariationId is 178766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.289C>A	p.Pro97Thr	missense_variant	Exon 3 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.289C>A	p.Pro97Thr	missense_variant	Exon 3 of 48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73595

AN:

151746

Hom.:

18252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.519

Gnomad ASJ

AF:

0.476

Gnomad EAS

AF:

0.735

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.572

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.490

Gnomad OTH

AF:

0.515

GnomAD2 exomes

AF:

0.525

AC:

132036

AN:

251288

AF XY:

0.525

show subpopulations

Gnomad AFR exome

AF:

0.403

Gnomad AMR exome

AF:

0.543

Gnomad ASJ exome

AF:

0.470

Gnomad EAS exome

AF:

0.746

Gnomad FIN exome

AF:

0.567

Gnomad NFE exome

AF:

0.493

Gnomad OTH exome

AF:

0.534

GnomAD4 exome

AF:

0.501

AC:

732667

AN:

1461370

Hom.:

185805

Cov.:

AF XY:

0.503

AC XY:

365670

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.402

AC:

13455

AN:

33452

American (AMR)

AF:

0.540

AC:

24151

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.469

AC:

12256

AN:

26122

East Asian (EAS)

AF:

0.743

AC:

29495

AN:

39688

South Asian (SAS)

AF:

0.545

AC:

47048

AN:

86250

European-Finnish (FIN)

AF:

0.563

AC:

30056

AN:

53404

Middle Eastern (MID)

AF:

0.548

AC:

3157

AN:

5762

European-Non Finnish (NFE)

AF:

0.488

AC:

542400

AN:

1111620

Other (OTH)

AF:

0.508

AC:

30649

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

18862

37723

56585

75446

94308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16012

32024

48036

64048

80060

<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:

0.485

AC:

73636

AN:

151864

Hom.:

18265

Cov.:

AF XY:

0.492

AC XY:

36526

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.404

AC:

16737

AN:

41388

American (AMR)

AF:

0.519

AC:

7921

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.476

AC:

1651

AN:

3466

East Asian (EAS)

AF:

0.735

AC:

3789

AN:

5156

South Asian (SAS)

AF:

0.560

AC:

2695

AN:

4812

European-Finnish (FIN)

AF:

0.572

AC:

6033

AN:

10544

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.491

AC:

33323

AN:

67934

Other (OTH)

AF:

0.520

AC:

1094

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1916

3832

5749

7665

9581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.486

Hom.:

66564

Bravo

AF:

0.478

TwinsUK

AF:

0.480

AC:

1779

ALSPAC

AF:

0.487

AC:

1875

ESP6500AA

AF:

0.414

AC:

1825

ESP6500EA

AF:

0.490

AC:

4213

ExAC

AF:

0.520

AC:

63186

Asia WGS

AF:

0.650

AC:

2260

AN:

3478

EpiCase

AF:

0.489

EpiControl

AF:

0.482

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 80% of patients studied by a panel of primary immunodeficiencies. Number of patients: 77. Only high quality variants are reported. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro97Thr in exon 3 of DOCK8: This variant is not expected to have clinical signi ficance because it has been identified in 49.0% (4213/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs529208). -

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Combined immunodeficiency due to DOCK8 deficiency

Benign:3

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. -

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:2Other:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.094

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;.;T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

T;T;T;T;T

MetaRNN

Benign

0.0000036

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.4

M;.;.;.;.

PhyloP100

3.2

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.5

.;D;.;D;D

REVEL

Benign

0.20

Sift

Benign

0.052

.;T;.;T;D

Sift4G

Uncertain

0.010

D;T;D;T;D

Polyphen

0.58

P;.;.;.;.

Vest4

0.23

MPC

0.16

ClinPred

0.048

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.30

gMVP

0.46

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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