5-169689340-G-A

Variant names:

• chr5-169689340-G-A
• rs72841138
• NM_004946.3:c.843+7G>A

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.843+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,613,588 control chromosomes in the GnomAD database, including 1,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (186 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1697 hom.)
• Consequence: DOCK2 NM_004946.3 splice_region, intron
• Scores: Splicing: ADA: 0.0003419
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.21
• Publications: 3 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=-0.53).
• BP6: Variant 5-169689340-G-A is Benign according to our data. Variant chr5-169689340-G-A is described in ClinVar as [Benign]. Clinvar id is 476020.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK2	NM_004946.3	c.843+7G>A		splice_region_variant, intron_variant	Intron 9 of 51	ENST00000520908.7	NP_004937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7	c.843+7G>A		splice_region_variant, intron_variant	Intron 9 of 51	2	NM_004946.3	ENSP00000429283.3
DOCK2	ENST00000524185.5	n.843+7G>A		splice_region_variant, intron_variant	Intron 9 of 52	1		ENSP00000428850.1
DOCK2	ENST00000519628.2	c.843+7G>A		splice_region_variant, intron_variant	Intron 9 of 27	3		ENSP00000428841.2
DOCK2	ENST00000522138.2	n.*353+7G>A		splice_region_variant, intron_variant	Intron 9 of 51	3		ENSP00000512484.1

Frequencies

GnomAD3 genomes AF: 0.0490 AC: 7453 AN: 152088 Hom.: 186 Cov.: 32

Gnomad AFR AF: 0.0685

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0384

Gnomad ASJ AF: 0.0585

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0490

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0390 AC: 9782 AN: 250966 AF XY: 0.0377

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.0556

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0304

Gnomad NFE exome AF: 0.0482

Gnomad OTH exome AF: 0.0506

GnomAD4 exome AF: 0.0451 AC: 65891 AN: 1461382 Hom.: 1697 Cov.: 30 AF XY: 0.0443 AC XY: 32195 AN XY: 727018

African (AFR) AF: 0.0716 AC: 2395 AN: 33464

American (AMR) AF: 0.0332 AC: 1486 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 1509 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39680

South Asian (SAS) AF: 0.0172 AC: 1479 AN: 86230

European-Finnish (FIN) AF: 0.0333 AC: 1781 AN: 53414

Middle Eastern (MID) AF: 0.0566 AC: 321 AN: 5672

European-Non Finnish (NFE) AF: 0.0488 AC: 54236 AN: 1111696

Other (OTH) AF: 0.0444 AC: 2681 AN: 60374

GnomAD4 genome AF: 0.0490 AC: 7459 AN: 152206 Hom.: 186 Cov.: 32 AF XY: 0.0468 AC XY: 3487 AN XY: 74442

African (AFR) AF: 0.0684 AC: 2840 AN: 41530

American (AMR) AF: 0.0384 AC: 587 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 203 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4822

European-Finnish (FIN) AF: 0.0254 AC: 269 AN: 10604

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0490 AC: 3331 AN: 67990

Other (OTH) AF: 0.0473 AC: 100 AN: 2112

Alfa AF: 0.0457 Hom.: 109

Bravo AF: 0.0520

Asia WGS AF: 0.0120 AC: 41 AN: 3476

EpiCase AF: 0.0527

EpiControl AF: 0.0496

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

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

- -

not provided Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.4
DANN	Benign	0.73
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.016
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: rs72841138; hg19: chr5-169116344;