rs1045176

Variant names:

• chr5-170083016-T-G
• rs1045176
• NM_004946.3:c.*158T>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.*158T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 875,472 control chromosomes in the GnomAD database, including 21,767 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 (7727 hom., cov: 31)
  • Exomes 𝑓: 0.17 (14040 hom.)
• Consequence: DOCK2 NM_004946.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK2	NM_004946.3	c.*158T>G		3_prime_UTR_variant	Exon 52 of 52	ENST00000520908.7	NP_004937.1
DOCK2	NR_156756.1	n.5754T>G		non_coding_transcript_exon_variant	Exon 53 of 53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7	c.*158T>G		3_prime_UTR_variant	Exon 52 of 52	2	NM_004946.3	ENSP00000429283.3

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40822 AN: 151708 Hom.: 7696 Cov.: 31

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.249

GnomAD4 exome AF: 0.169 AC: 122086 AN: 723646 Hom.: 14040 Cov.: 10 AF XY: 0.170 AC XY: 62873 AN XY: 370638

African (AFR) AF: 0.541 AC: 9758 AN: 18040

American (AMR) AF: 0.204 AC: 5666 AN: 27816

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 3184 AN: 17298

East Asian (EAS) AF: 0.435 AC: 13854 AN: 31874

South Asian (SAS) AF: 0.220 AC: 12280 AN: 55788

European-Finnish (FIN) AF: 0.179 AC: 5794 AN: 32286

Middle Eastern (MID) AF: 0.180 AC: 481 AN: 2670

European-Non Finnish (NFE) AF: 0.128 AC: 64446 AN: 502704

Other (OTH) AF: 0.188 AC: 6623 AN: 35170

GnomAD4 genome AF: 0.269 AC: 40906 AN: 151826 Hom.: 7727 Cov.: 31 AF XY: 0.271 AC XY: 20119 AN XY: 74202

African (AFR) AF: 0.526 AC: 21780 AN: 41372

American (AMR) AF: 0.201 AC: 3067 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3464

East Asian (EAS) AF: 0.446 AC: 2275 AN: 5096

South Asian (SAS) AF: 0.240 AC: 1158 AN: 4816

European-Finnish (FIN) AF: 0.193 AC: 2038 AN: 10560

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9170 AN: 67928

Other (OTH) AF: 0.257 AC: 541 AN: 2108

Alfa AF: 0.201 Hom.: 2027

Bravo AF: 0.282

Asia WGS AF: 0.337 AC: 1174 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		-0.085
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: rs1045176; hg19: chr5-169510020; COSMIC: COSV56996430; COSMIC: COSV56996430;