rs3763048

Positions:

• chr5-170034543-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004946.3(DOCK2):​c.3612C>T​(p.Thr1204=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,613,754 control chromosomes in the GnomAD database, including 114,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15154 hom., cov: 33)
  • Exomes 𝑓: 0.36 (98925 hom.)
• Consequence: DOCK2 NM_004946.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -5.00

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 5-170034543-C-T is Benign according to our data. Variant chr5-170034543-C-T is described in ClinVar as [Benign]. Clinvar id is 1165009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.3612C>T	p.Thr1204=	synonymous_variant	35/52	ENST00000520908.7
DOCK2	NR_156756.1	n.3715C>T		non_coding_transcript_exon_variant	36/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.3612C>T	p.Thr1204=	synonymous_variant	35/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65149 AN: 151956 Hom.: 15138 Cov.: 33

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.404

GnomAD3 exomes AF: 0.397 AC: 99645 AN: 250920 Hom.: 21024 AF XY: 0.396 AC XY: 53733 AN XY: 135594

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.580

Gnomad SAS exome AF: 0.484

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.361 AC: 527089 AN: 1461680 Hom.: 98925 Cov.: 41 AF XY: 0.364 AC XY: 264313 AN XY: 727130

Gnomad4 AFR exome AF: 0.613

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.561

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.335

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.429 AC: 65222 AN: 152074 Hom.: 15154 Cov.: 33 AF XY: 0.430 AC XY: 31984 AN XY: 74324

Gnomad4 AFR AF: 0.609

Gnomad4 AMR AF: 0.367

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.576

Gnomad4 SAS AF: 0.485

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.408

Alfa AF: 0.362 Hom.: 16662

Bravo AF: 0.442

Asia WGS AF: 0.533 AC: 1856 AN: 3478

EpiCase AF: 0.346

EpiControl AF: 0.357

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DOCK2 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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	-0.67
CADD	Benign	0.19
DANN	Benign	0.63
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: rs3763048; hg19: chr5-169461547; COSMIC: COSV56944261; COSMIC: COSV56944261;