rs17647491

Variant names:

• chr5-170056702-C-T
• rs17647491
• NM_004946.3:c.4314C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_004946.3(DOCK2):​c.4314C>T​(p.Tyr1438Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,988 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (27 hom., cov: 32)
  • Exomes 𝑓: 0.017 (226 hom.)
• Consequence: DOCK2 NM_004946.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.92
• Publications: 4 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-170056702-C-T is Benign according to our data. Variant chr5-170056702-C-T is described in ClinVar as Benign. ClinVar VariationId is 476014.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.014 (2134/152244) while in subpopulation NFE AF = 0.0211 (1433/68022). AF 95% confidence interval is 0.0202. There are 27 homozygotes in GnomAd4. There are 975 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

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.4314C>T	p.Tyr1438Tyr	synonymous	Exon 43 of 52	NP_004937.1
	DOCK2	NR_156756.1		n.4417C>T		non_coding_transcript_exon	Exon 44 of 53

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.4314C>T	p.Tyr1438Tyr	synonymous	Exon 43 of 52	ENSP00000429283.3
	DOCK2	ENST00000524185.5	TSL:1	n.*1269C>T		non_coding_transcript_exon	Exon 44 of 53	ENSP00000428850.1
	DOCK2	ENST00000524185.5	TSL:1	n.*1269C>T		3_prime_UTR	Exon 44 of 53	ENSP00000428850.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2134 AN: 152126 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0124 AC: 3104 AN: 251276 AF XY: 0.0117

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00871

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0210

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0165 AC: 24121 AN: 1461744 Hom.: 226 Cov.: 30 AF XY: 0.0160 AC XY: 11633 AN XY: 727172

African (AFR) AF: 0.00272 AC: 91 AN: 33480

American (AMR) AF: 0.00845 AC: 378 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00570 AC: 149 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00234 AC: 202 AN: 86252

European-Finnish (FIN) AF: 0.0205 AC: 1096 AN: 53412

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0192 AC: 21396 AN: 1111886

Other (OTH) AF: 0.0133 AC: 802 AN: 60396

GnomAD4 genome AF: 0.0140 AC: 2134 AN: 152244 Hom.: 27 Cov.: 32 AF XY: 0.0131 AC XY: 975 AN XY: 74450

African (AFR) AF: 0.00315 AC: 131 AN: 41536

American (AMR) AF: 0.0192 AC: 294 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.0166 AC: 176 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1433 AN: 68022

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0170 Hom.: 23

Bravo AF: 0.0125

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0151

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DOCK2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.5
DANN	Benign	0.58
PhyloP100		-1.9
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17647491; hg19: chr5-169483706;