9-421032-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_203447.4(DOCK8):c.4107C>G(p.Leu1369Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 1,613,794 control chromosomes in the GnomAD database, including 271,763 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. L1369L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.45 ( 18331 hom., cov: 32)

Exomes 𝑓: 0.58 ( 253432 hom. )

Consequence

DOCK8
NM_203447.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.58

Publications

20 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 9-421032-C-G is Benign according to our data. Variant chr9-421032-C-G is described in ClinVar as Benign. ClinVar VariationId is 178769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.59 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.4107C>G	p.Leu1369Leu	synonymous_variant	Exon 32 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.4107C>G	p.Leu1369Leu	synonymous_variant	Exon 32 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes

AF:

0.450

AC:

68338

AN:

151964

Hom.:

18331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.723

Gnomad AMR

AF:

0.457

Gnomad ASJ

AF:

0.520

Gnomad EAS

AF:

0.484

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.463

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.619

Gnomad OTH

AF:

0.483

GnomAD2 exomes

AF:

0.509

AC:

127876

AN:

251430

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.392

Gnomad ASJ exome

AF:

0.512

Gnomad EAS exome

AF:

0.490

Gnomad FIN exome

AF:

0.485

Gnomad NFE exome

AF:

0.622

Gnomad OTH exome

AF:

0.547

GnomAD4 exome

AF:

0.580

AC:

847787

AN:

1461710

Hom.:

253432

Cov.:

AF XY:

0.577

AC XY:

419256

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.136

AC:

4556

AN:

33474

American (AMR)

AF:

0.401

AC:

17931

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.513

AC:

13399

AN:

26136

East Asian (EAS)

AF:

0.424

AC:

16852

AN:

39700

South Asian (SAS)

AF:

0.432

AC:

37278

AN:

86252

European-Finnish (FIN)

AF:

0.491

AC:

26231

AN:

53418

Middle Eastern (MID)

AF:

0.534

AC:

3077

AN:

5758

European-Non Finnish (NFE)

AF:

0.625

AC:

695228

AN:

1111854

Other (OTH)

AF:

0.550

AC:

33235

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

20198

40396

60594

80792

100990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18248

36496

54744

72992

91240

<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:

0.449

AC:

68350

AN:

152084

Hom.:

18331

Cov.:

AF XY:

0.442

AC XY:

32864

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.150

AC:

6222

AN:

41496

American (AMR)

AF:

0.457

AC:

6984

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.520

AC:

1806

AN:

3470

East Asian (EAS)

AF:

0.484

AC:

2496

AN:

5162

South Asian (SAS)

AF:

0.425

AC:

2052

AN:

4826

European-Finnish (FIN)

AF:

0.463

AC:

4885

AN:

10546

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.619

AC:

42056

AN:

67974

Other (OTH)

AF:

0.482

AC:

1018

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1682

3363

5045

6726

8408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

604

1208

1812

2416

3020

<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:

0.564

Hom.:

8219

Bravo

AF:

0.437

Asia WGS

AF:

0.396

AC:

1377

AN:

3478

EpiCase

AF:

0.614

EpiControl

AF:

0.616

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu1369Leu in exon 32 of DOCK8: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 38.7% (3325/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2297079). -

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 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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:2Other: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. -

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

- -

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

-0.33

CADD

Benign

7.1

(source)

DANN

Benign

0.71

PhyloP100

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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