9-340229-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_203447.4(DOCK8):c.1587C>G(p.Pro529Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,614,102 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P529P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 3 hom. )

Consequence

DOCK8
NM_203447.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.694

Publications

3 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=-0.37).

BP6

Variant 9-340229-C-G is Benign according to our data. Variant chr9-340229-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 390080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.694 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0027 (411/152240) while in subpopulation AFR AF = 0.00932 (387/41540). AF 95% confidence interval is 0.00855. There are 1 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.1587C>G	p.Pro529Pro	synonymous_variant	Exon 14 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.1587C>G	p.Pro529Pro	synonymous_variant	Exon 14 of 48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

411

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00934

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.000752

AC:

189

AN:

251300

AF XY:

0.000501

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000257

AC:

375

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

150

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00914

AC:

306

AN:

33478

American (AMR)

AF:

0.000358

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111984

Other (OTH)

AF:

0.000596

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00270

AC:

411

AN:

152240

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

185

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00932

AC:

387

AN:

41540

American (AMR)

AF:

0.00118

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000128

Hom.:

Bravo

AF:

0.00303

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DOCK8: BP4, BP7 -

Jan 07, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Jan 27, 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

-0.37

CADD

Benign

0.024

(source)

DANN

Benign

0.71

PhyloP100

-0.69

Mutation Taster

=100/0

polymorphism

(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