rs6555882

Positions:

• chr5-170042084-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_004946.3(DOCK2):​c.3828G>C​(p.Leu1276=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,613,438 control chromosomes in the GnomAD database, including 3,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.088 (1474 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1719 hom.)
• Consequence: DOCK2 NM_004946.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.46

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-170042084-G-C is Benign according to our data. Variant chr5-170042084-G-C is described in ClinVar as [Benign]. Clinvar id is 476012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.3828G>C	p.Leu1276=	synonymous_variant	38/52	ENST00000520908.7
DOCK2	NR_156756.1	n.3931G>C		non_coding_transcript_exon_variant	39/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.3828G>C	p.Leu1276=	synonymous_variant	38/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13291 AN: 152002 Hom.: 1467 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0432

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0727

GnomAD3 exomes AF: 0.0368 AC: 9207 AN: 250318 Hom.: 669 AF XY: 0.0333 AC XY: 4502 AN XY: 135304

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.0254

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0410

Gnomad FIN exome AF: 0.00662

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0242 AC: 35348 AN: 1461318 Hom.: 1719 Cov.: 31 AF XY: 0.0243 AC XY: 17634 AN XY: 726934

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.0265

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0425

Gnomad4 FIN exome AF: 0.00755

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0359

GnomAD4 genome AF: 0.0876 AC: 13324 AN: 152120 Hom.: 1474 Cov.: 32 AF XY: 0.0847 AC XY: 6301 AN XY: 74378

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.0410

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0432

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0720

Alfa AF: 0.0385 Hom.: 138

Bravo AF: 0.0991

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.0206

EpiControl AF: 0.0229

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	-0.46
CADD	Benign	7.0
DANN	Benign	0.55

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: rs6555882; hg19: chr5-169469088;