dbSNP rs34098809: DOCK8:p.Glu1737Glu (chr9-439376-G-A) – ACMG Classification: Benign (-19 pts)

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.5211G>A(p.Glu1737Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,613,434 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 29 hom. )

Consequence

DOCK8
NM_203447.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.253

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, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
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

new If you want to explore the variant's impact on the transcript NM_203447.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.41).

BP6

Variant 9-439376-G-A is Benign according to our data. Variant chr9-439376-G-A is described in ClinVar as Benign. ClinVar VariationId is 137150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.253 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00931 (1418/152262) while in subpopulation AFR AF = 0.0257 (1068/41544). AF 95% confidence interval is 0.0244. There are 17 homozygotes in GnomAd4. There are 655 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203447.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK8	NM_203447.4	MANE Select	c.5211G>A	p.Glu1737Glu	synonymous	Exon 40 of 48	NP_982272.2	Q8NF50-1
DOCK8	NM_001193536.2		c.5007G>A	p.Glu1669Glu	synonymous	Exon 39 of 47	NP_001180465.1	Q8NF50-3
DOCK8	NM_001190458.2		c.4911G>A	p.Glu1637Glu	synonymous	Exon 38 of 46	NP_001177387.1	Q8NF50-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.5211G>A	p.Glu1737Glu	synonymous	Exon 40 of 48	ENSP00000394888.3	Q8NF50-1
DOCK8	ENST00000469391.5	TSL:1	c.4911G>A	p.Glu1637Glu	synonymous	Exon 38 of 46	ENSP00000419438.1	Q8NF50-4
DOCK8	ENST00000382329.2	TSL:1	c.4911G>A	p.Glu1637Glu	synonymous	Exon 39 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes

AF:

0.00926

AC:

1409

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00929

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.00450

AC:

1127

AN:

250594

AF XY:

0.00403

show subpopulations

Gnomad AFR exome

AF:

0.0262

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00136

Gnomad NFE exome

AF:

0.00283

Gnomad OTH exome

AF:

0.00832

GnomAD4 exome

AF:

0.00278

AC:

4059

AN:

1461172

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

1959

AN XY:

726906

show subpopulations

African (AFR)

AF:

0.0286

AC:

959

AN:

33476

American (AMR)

AF:

0.00769

AC:

344

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000870

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00108

AC:

AN:

52904

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00192

AC:

2140

AN:

1111922

Other (OTH)

AF:

0.00598

AC:

361

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

245

491

736

982

1227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00931

AC:

1418

AN:

152262

Hom.:

Cov.:

AF XY:

0.00880

AC XY:

655

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0257

AC:

1068

AN:

41544

American (AMR)

AF:

0.00928

AC:

142

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00228

AC:

155

AN:

68024

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00549

Hom.:

Bravo

AF:

0.0105

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00373

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Combined immunodeficiency due to DOCK8 deficiency (1)

not provided (1)

Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.0

(source)

DANN

Benign

0.60

PhyloP100

0.25

Mutation Taster

=96/4

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over