5-169718723-C-T

Variant names:

• chr5-169718723-C-T
• rs35530753
• NM_004946.3:c.2199C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_004946.3(DOCK2):​c.2199C>T​(p.Ile733Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,902 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (16 hom.)
• Consequence: DOCK2 NM_004946.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.237

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-169718723-C-T is Benign according to our data. Variant chr5-169718723-C-T is described in ClinVar as [Benign]. Clinvar id is 476005.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.237 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00701 (1068/152260) while in subpopulation AFR AF = 0.0235 (975/41532). AF 95% confidence interval is 0.0223. There are 10 homozygotes in GnomAd4. There are 503 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK2	NM_004946.3	c.2199C>T	p.Ile733Ile	synonymous_variant	Exon 22 of 52	ENST00000520908.7	NP_004937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7	c.2199C>T	p.Ile733Ile	synonymous_variant	Exon 22 of 52	2	NM_004946.3	ENSP00000429283.3

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1066 AN: 152142 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00226 AC: 566 AN: 250938 AF XY: 0.00179

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000948 AC: 1385 AN: 1461642 Hom.: 16 Cov.: 30 AF XY: 0.000827 AC XY: 601 AN XY: 727116

Gnomad4 AFR exome AF: 0.0239 AC: 800 AN: 33470

Gnomad4 AMR exome AF: 0.00174 AC: 78 AN: 44718

Gnomad4 ASJ exome AF: 0.0113 AC: 296 AN: 26128

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39652

Gnomad4 SAS exome AF: 0.0000928 AC: 8 AN: 86248

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53414

Gnomad4 NFE exome AF: 0.0000459 AC: 51 AN: 1111866

Gnomad4 Remaining exome AF: 0.00243 AC: 147 AN: 60380

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152260 Hom.: 10 Cov.: 32 AF XY: 0.00676 AC XY: 503 AN XY: 74460

Gnomad4 AFR AF: 0.0235 AC: 0.0234759 AN: 0.0234759

Gnomad4 AMR AF: 0.00255 AC: 0.00255102 AN: 0.00255102

Gnomad4 ASJ AF: 0.0101 AC: 0.0100865 AN: 0.0100865

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000441 AC: 0.0000440995 AN: 0.0000440995

Gnomad4 OTH AF: 0.00757 AC: 0.00756859 AN: 0.00756859

Alfa AF: 0.00529 Hom.: 2

Bravo AF: 0.00807

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DOCK2 deficiency Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.4
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs35530753; hg19: chr5-169145727;