rs35393134

chr5-169674341-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004946.3(DOCK2):c.366C>T(p.Tyr122=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,614,094 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (58 hom.)
• Consequence: DOCK2 NM_004946.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.38

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=-0.55).
• BP6: Variant 5-169674341-C-T is Benign according to our data. Variant chr5-169674341-C-T is described in ClinVar as [Benign]. Clinvar id is 476011.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.366C>T	p.Tyr122=	synonymous_variant	6/52	ENST00000520908.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.366C>T	p.Tyr122=	synonymous_variant	6/52	2	NM_004946.3	P1
DOCK2	ENST00000524185.5	c.366C>T	p.Tyr122=	synonymous_variant, NMD_transcript_variant	6/53	1
DOCK2	ENST00000519628.2	c.366C>T	p.Tyr122=	synonymous_variant	6/28	3
DOCK2	ENST00000522138.2	c.366C>T	p.Tyr122=	synonymous_variant, NMD_transcript_variant	6/52	3

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2237 AN: 152134 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00411 AC: 1031 AN: 251142 Hom.: 22 AF XY: 0.00301 AC XY: 408 AN XY: 135708

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00181 AC: 2640 AN: 1461842 Hom.: 58 Cov.: 31 AF XY: 0.00160 AC XY: 1164 AN XY: 727214

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.00394

GnomAD4 genome AF: 0.0148 AC: 2248 AN: 152252 Hom.: 63 Cov.: 32 AF XY: 0.0137 AC XY: 1018 AN XY: 74446

Gnomad4 AFR AF: 0.0501

Gnomad4 AMR AF: 0.00640

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00686 Hom.: 7

Bravo AF: 0.0168

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

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	-0.55
Cadd	Benign	2.8
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35393134; hg19: chr5-169101345;