9-446352-G-C

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.5581-18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,605,654 control chromosomes in the GnomAD database, including 386,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 29786 hom., cov: 33)

Exomes 𝑓: 0.70 ( 357148 hom. )

Consequence

DOCK8
NM_203447.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.34

Publications

11 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 (BayesDel_noAF=-0.91).

BP6

Variant 9-446352-G-C is Benign according to our data. Variant chr9-446352-G-C is described in ClinVar as [Benign]. Clinvar id is 263270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.5581-18G>C		intron_variant	Intron 43 of 47	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.5581-18G>C		intron_variant	Intron 43 of 47	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

90367

AN:

151964

Hom.:

29778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.291

Gnomad AMI

AF:

0.609

Gnomad AMR

AF:

0.738

Gnomad ASJ

AF:

0.627

Gnomad EAS

AF:

0.985

Gnomad SAS

AF:

0.676

Gnomad FIN

AF:

0.690

Gnomad MID

AF:

0.696

Gnomad NFE

AF:

0.694

Gnomad OTH

AF:

0.608

GnomAD2 exomes

AF:

0.700

AC:

175532

AN:

250910

AF XY:

0.699

show subpopulations

Gnomad AFR exome

AF:

0.277

Gnomad AMR exome

AF:

0.810

Gnomad ASJ exome

AF:

0.618

Gnomad EAS exome

AF:

0.985

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.697

Gnomad OTH exome

AF:

0.700

GnomAD4 exome

AF:

0.695

AC:

1010939

AN:

1453574

Hom.:

357148

Cov.:

AF XY:

0.695

AC XY:

502838

AN XY:

723784

show subpopulations

African (AFR)

AF:

0.277

AC:

9219

AN:

33280

American (AMR)

AF:

0.801

AC:

35811

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.620

AC:

16153

AN:

26070

East Asian (EAS)

AF:

0.991

AC:

39313

AN:

39676

South Asian (SAS)

AF:

0.667

AC:

57344

AN:

86024

European-Finnish (FIN)

AF:

0.698

AC:

37257

AN:

53372

Middle Eastern (MID)

AF:

0.626

AC:

3611

AN:

5764

European-Non Finnish (NFE)

AF:

0.698

AC:

770985

AN:

1104604

Other (OTH)

AF:

0.686

AC:

41246

AN:

60082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

13167

26333

39500

52666

65833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.594

AC:

90404

AN:

152080

Hom.:

29786

Cov.:

AF XY:

0.601

AC XY:

44708

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.291

AC:

12068

AN:

41482

American (AMR)

AF:

0.738

AC:

11288

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.627

AC:

2176

AN:

3468

East Asian (EAS)

AF:

0.985

AC:

5103

AN:

5180

South Asian (SAS)

AF:

0.676

AC:

3265

AN:

4828

European-Finnish (FIN)

AF:

0.690

AC:

7304

AN:

10578

Middle Eastern (MID)

AF:

0.690

AC:

203

AN:

294

European-Non Finnish (NFE)

AF:

0.694

AC:

47152

AN:

67940

Other (OTH)

AF:

0.613

AC:

1290

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1635

3271

4906

6542

8177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.588

Hom.:

3708

Bravo

AF:

0.586

Asia WGS

AF:

0.800

AC:

2781

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 94% of patients studied by a panel of primary immunodeficiencies. Number of patients: 90. Only high quality variants are reported. -

not provided

Benign:2

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

- -

Combined immunodeficiency due to DOCK8 deficiency

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.91

CADD

Benign

0.86

(source)

DANN

Benign

0.52

PhyloP100

-1.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

9-446352-G-C

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