Genetic Variant DOCK2:c.*530G>A (chr5-170083388-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004946.3(DOCK2):c.*530G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 152,364 control chromosomes in the GnomAD database, including 7,658 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 7653 hom., cov: 32)

Exomes 𝑓: 0.13 ( 5 hom. )

Consequence

DOCK2
NM_004946.3 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0190

Publications

2 publications found

Variant links:

Genes affected

DOCK2 (HGNC:2988): (dedicator of cytokinesis 2) The protein encoded by this gene belongs to the CDM protein family. It is specifically expressed in hematopoietic cells and is predominantly expressed in peripheral blood leukocytes. The protein is involved in remodeling of the actin cytoskeleton required for lymphocyte migration in response to chemokine signaling. It activates members of the Rho family of GTPases, for example RAC1 and RAC2, by acting as a guanine nucleotide exchange factor (GEF) to exchange bound GDP for free GTP. Mutations in this gene result in immunodeficiency 40 (IMD40), a combined form of immunodeficiency that affects T cell number and function, also with variable defects in B cell and NK cell function. [provided by RefSeq, May 2018]

DOCK2 Gene-Disease associations (from GenCC):

DOCK2 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

DOCK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004946.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	NM_004946.3	MANE Select	c.*530G>A		downstream_gene	N/A	NP_004937.1
	DOCK2	NR_156756.1		n.*6G>A		downstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.*530G>A	downstream_gene	N/A	ENSP00000429283.3
DOCK2	ENST00000519868.1	TSL:2	n.*11G>A	downstream_gene	N/A
DOCK2	ENST00000520450.6	TSL:2	n.*11G>A	downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.266

AC:

40375

AN:

151882

Hom.:

7624

Cov.:

show subpopulations

Gnomad AFR

AF:

0.525

Gnomad AMI

AF:

0.183

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.448

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.244

GnomAD4 exome

AF:

0.129

AC:

AN:

364

Hom.:

Cov.:

AF XY:

0.137

AC XY:

AN XY:

226

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

0.263

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.192

AC:

AN:

European-Finnish (FIN)

AF:

0.333

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0993

AC:

AN:

272

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

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:

0.266

AC:

40457

AN:

152000

Hom.:

7653

Cov.:

AF XY:

0.268

AC XY:

19906

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.525

AC:

21745

AN:

41428

American (AMR)

AF:

0.196

AC:

2999

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

632

AN:

3468

East Asian (EAS)

AF:

0.449

AC:

2315

AN:

5158

South Asian (SAS)

AF:

0.238

AC:

1145

AN:

4808

European-Finnish (FIN)

AF:

0.191

AC:

2013

AN:

10566

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.130

AC:

8867

AN:

67966

Other (OTH)

AF:

0.251

AC:

530

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1272

2544

3817

5089

6361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.168

Hom.:

1734

Bravo

AF:

0.278

Asia WGS

AF:

0.334

AC:

1164

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.1

(source)

DANN

Benign

0.28

PhyloP100

0.019

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over