dbSNP rs6555882: DOCK2:p.Leu1276Leu (chr5-170042084-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_004946.3(DOCK2):c.3828G>C(p.Leu1276Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,613,438 control chromosomes in the GnomAD database, including 3,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.088 ( 1474 hom., cov: 32)

Exomes 𝑓: 0.024 ( 1719 hom. )

Consequence

DOCK2
NM_004946.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.46

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 5-170042084-G-C is Benign according to our data. Variant chr5-170042084-G-C is described in ClinVar as [Benign]. Clinvar id is 476012.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=2.46 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK2	NM_004946.3 link	c.3828G>C	p.Leu1276Leu	synonymous_variant	Exon 38 of 52	ENST00000520908.7	NP_004937.1	Q92608-1Q5XG91
DOCK2	NR_156756.1 link	n.3931G>C		non_coding_transcript_exon_variant	Exon 39 of 53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7 link	c.3828G>C	p.Leu1276Leu	synonymous_variant	Exon 38 of 52	2	NM_004946.3	ENSP00000429283.3		Q92608-1

Frequencies

GnomAD3 genomes

AF:

0.0874

AC:

13291

AN:

152002

Hom.:

1467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.262

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0412

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0432

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0727

GnomAD3 exomes

AF:

0.0368

AC:

9207

AN:

250318

Hom.:

669

AF XY:

0.0333

AC XY:

4502

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.271

Gnomad AMR exome

AF:

0.0254

Gnomad ASJ exome

AF:

0.0269

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0410

Gnomad FIN exome

AF:

0.00662

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0311

GnomAD4 exome

AF:

0.0242

AC:

35348

AN:

1461318

Hom.:

1719

Cov.:

AF XY:

0.0243

AC XY:

17634

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.272

Gnomad4 AMR exome

AF:

0.0265

Gnomad4 ASJ exome

AF:

0.0261

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0425

Gnomad4 FIN exome

AF:

0.00755

Gnomad4 NFE exome

AF:

0.0160

Gnomad4 OTH exome

AF:

0.0359

GnomAD4 genome

AF:

0.0876

AC:

13324

AN:

152120

Hom.:

1474

Cov.:

AF XY:

0.0847

AC XY:

6301

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.262

Gnomad4 AMR

AF:

0.0410

Gnomad4 ASJ

AF:

0.0265

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0432

Gnomad4 FIN

AF:

0.00499

Gnomad4 NFE

AF:

0.0181

Gnomad4 OTH

AF:

0.0720

Alfa

AF:

0.0385

Hom.:

138

Bravo

AF:

0.0991

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0206

EpiControl

AF:

0.0229

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

DOCK2 deficiency

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

-0.46

CADD

Benign

7.0

DANN

Benign

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over