chr5-170042084-G-C

Variant names:

• chr5-170042084-G-C
• rs6555882
• NM_004946.3:c.3828G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_004946.3(DOCK2):​c.3828G>C​(p.Leu1276Leu) 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
• Publications: 6 publications found

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]

DOCK2 Gene-Disease associations (from GenCC):

• DOCK2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004946.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	NM_004946.3	MANE Select	c.3828G>C	p.Leu1276Leu	synonymous	Exon 38 of 52	NP_004937.1
	DOCK2	NR_156756.1		n.3931G>C		non_coding_transcript_exon	Exon 39 of 53

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.3828G>C	p.Leu1276Leu	synonymous	Exon 38 of 52	ENSP00000429283.3
	DOCK2	ENST00000524185.5	TSL:1	n.*783G>C		non_coding_transcript_exon	Exon 39 of 53	ENSP00000428850.1
	DOCK2	ENST00000524185.5	TSL:1	n.*783G>C		3_prime_UTR	Exon 39 of 53	ENSP00000428850.1

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

GnomAD2 exomes AF: 0.0368 AC: 9207 AN: 250318 AF XY: 0.0333

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 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

African (AFR) AF: 0.272 AC: 9085 AN: 33450

American (AMR) AF: 0.0265 AC: 1183 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 681 AN: 26124

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39658

South Asian (SAS) AF: 0.0425 AC: 3660 AN: 86218

European-Finnish (FIN) AF: 0.00755 AC: 403 AN: 53354

Middle Eastern (MID) AF: 0.0663 AC: 382 AN: 5758

European-Non Finnish (NFE) AF: 0.0160 AC: 17786 AN: 1111692

Other (OTH) AF: 0.0359 AC: 2164 AN: 60352

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

African (AFR) AF: 0.262 AC: 10875 AN: 41442

American (AMR) AF: 0.0410 AC: 627 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0432 AC: 208 AN: 4814

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10620

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0181 AC: 1229 AN: 67986

Other (OTH) AF: 0.0720 AC: 152 AN: 2112

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.0
DANN	Benign	0.55
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6555882; hg19: chr5-169469088;