rs36028557

chr5-169985875-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_004946.3(DOCK2):c.2946G>A(p.Lys982=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,610,970 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (41 hom.)
• Consequence: DOCK2 NM_004946.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.587

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-169985875-G-A is Benign according to our data. Variant chr5-169985875-G-A is described in ClinVar as [Benign]. Clinvar id is 476009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.587 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2250/152306) while in subpopulation AFR AF= 0.0498 (2069/41560). AF 95% confidence interval is 0.048. There are 52 homozygotes in gnomad4. There are 1023 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.2946G>A	p.Lys982=	synonymous_variant	29/52	ENST00000520908.7
DOCK2	NR_156756.1	n.2998G>A		non_coding_transcript_exon_variant	29/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.2946G>A	p.Lys982=	synonymous_variant	29/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2248 AN: 152188 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00358 AC: 897 AN: 250384 Hom.: 17 AF XY: 0.00248 AC XY: 335 AN XY: 135318

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000986

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00157 AC: 2292 AN: 1458664 Hom.: 41 Cov.: 30 AF XY: 0.00136 AC XY: 984 AN XY: 725688

Gnomad4 AFR exome AF: 0.0506

Gnomad4 AMR exome AF: 0.00323

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.00372

GnomAD4 genome AF: 0.0148 AC: 2250 AN: 152306 Hom.: 52 Cov.: 32 AF XY: 0.0137 AC XY: 1023 AN XY: 74482

Gnomad4 AFR AF: 0.0498

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00608 Hom.: 10

Bravo AF: 0.0174

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DOCK2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	4.4
Dann	Benign	0.42

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

Other links and lift over

dbSNP: rs36028557; hg19: chr5-169412879;