rs262838

Variant names:

• chr5-169747690-A-G
• rs262838
• NM_004946.3:c.2376+186A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004946.3(DOCK2):​c.2376+186A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 152,124 control chromosomes in the GnomAD database, including 11,413 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 0.32 (11413 hom., cov: 33)
• Consequence: DOCK2 NM_004946.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0190
• Publications: 4 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK2	NM_004946.3	c.2376+186A>G		intron_variant	Intron 23 of 51	ENST00000520908.7	NP_004937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7	c.2376+186A>G		intron_variant	Intron 23 of 51	2	NM_004946.3	ENSP00000429283.3

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48988 AN: 152006 Hom.: 11370 Cov.: 33

Gnomad AFR AF: 0.641

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.323 AC: 49088 AN: 152124 Hom.: 11413 Cov.: 33 AF XY: 0.327 AC XY: 24316 AN XY: 74386

African (AFR) AF: 0.641 AC: 26592 AN: 41468

American (AMR) AF: 0.402 AC: 6140 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 810 AN: 3466

East Asian (EAS) AF: 0.272 AC: 1407 AN: 5176

South Asian (SAS) AF: 0.389 AC: 1880 AN: 4832

European-Finnish (FIN) AF: 0.164 AC: 1742 AN: 10596

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9712 AN: 68000

Other (OTH) AF: 0.312 AC: 659 AN: 2114

Alfa AF: 0.249 Hom.: 2699

Bravo AF: 0.355

Asia WGS AF: 0.349 AC: 1213 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.13
DANN	Benign	0.45
PhyloP100		-0.019
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs262838; hg19: chr5-169174694;