chr5-170041239-A-G

Variant names:

• chr5-170041239-A-G
• rs2270895
• NM_004946.3:c.3756+94A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004946.3(DOCK2):​c.3756+94A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,167,328 control chromosomes in the GnomAD database, including 135,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.42 (14571 hom., cov: 32)
  • Exomes 𝑓: 0.48 (120738 hom.)
• Consequence: DOCK2 NM_004946.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.255
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-170041239-A-G is Benign according to our data. Variant chr5-170041239-A-G is described in ClinVar as Benign. ClinVar VariationId is 2688034.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 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.3756+94A>G		intron	N/A	NP_004937.1
	DOCK2	NR_156756.1		n.3859+94A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.3756+94A>G		intron	N/A	ENSP00000429283.3
	DOCK2	ENST00000524185.5	TSL:1	n.*711+94A>G		intron	N/A	ENSP00000428850.1
	DOCK2	ENST00000961039.1		c.3717+94A>G		intron	N/A	ENSP00000631098.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63735 AN: 151866 Hom.: 14552 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.481 AC: 488104 AN: 1015344 Hom.: 120738 AF XY: 0.485 AC XY: 250934 AN XY: 517830

African (AFR) AF: 0.231 AC: 5546 AN: 24022

American (AMR) AF: 0.544 AC: 19203 AN: 35270

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 11209 AN: 22676

East Asian (EAS) AF: 0.621 AC: 21759 AN: 35028

South Asian (SAS) AF: 0.567 AC: 41351 AN: 72886

European-Finnish (FIN) AF: 0.530 AC: 24285 AN: 45854

Middle Eastern (MID) AF: 0.522 AC: 2569 AN: 4922

European-Non Finnish (NFE) AF: 0.467 AC: 340858 AN: 729226

Other (OTH) AF: 0.469 AC: 21324 AN: 45460

GnomAD4 genome AF: 0.420 AC: 63781 AN: 151984 Hom.: 14571 Cov.: 32 AF XY: 0.430 AC XY: 31959 AN XY: 74286

African (AFR) AF: 0.236 AC: 9800 AN: 41476

American (AMR) AF: 0.474 AC: 7246 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1709 AN: 3468

East Asian (EAS) AF: 0.620 AC: 3201 AN: 5162

South Asian (SAS) AF: 0.573 AC: 2760 AN: 4818

European-Finnish (FIN) AF: 0.548 AC: 5770 AN: 10538

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31815 AN: 67928

Other (OTH) AF: 0.426 AC: 899 AN: 2108

Alfa AF: 0.455 Hom.: 25989

Bravo AF: 0.409

Asia WGS AF: 0.620 AC: 2157 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.82
PhyloP100		0.26
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: rs2270895; hg19: chr5-169468243; COSMIC: COSV56996219;