rs201626676

Variant names:

• chr5-169708202-A-G
• rs201626676
• NM_004946.3:c.1417A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004946.3(DOCK2):​c.1417A>G​(p.Met473Val) variant causes a missense change. The variant allele was found at a frequency of 0.00209 in 1,614,058 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (85 hom.)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.44
• Publications: 2 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003529787).
• BP6: Variant 5-169708202-A-G is Benign according to our data. Variant chr5-169708202-A-G is described in ClinVar as Benign. ClinVar VariationId is 476000.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00122 (186/152382) while in subpopulation SAS AF = 0.037 (179/4834). AF 95% confidence interval is 0.0326. There are 6 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	NM_004946.3	MANE Select	c.1417A>G	p.Met473Val	missense	Exon 15 of 52	NP_004937.1	Q92608-1
	DOCK2	NR_156756.1		n.1469A>G		non_coding_transcript_exon	Exon 15 of 53

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.1417A>G	p.Met473Val	missense	Exon 15 of 52	ENSP00000429283.3	Q92608-1
	DOCK2	ENST00000524185.5	TSL:1	n.1417A>G		non_coding_transcript_exon	Exon 15 of 53	ENSP00000428850.1	E5RFJ0
	DOCK2	ENST00000961039.1		c.1417A>G	p.Met473Val	missense	Exon 15 of 52	ENSP00000631098.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 188 AN: 152264 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00432 AC: 1083 AN: 250656 AF XY: 0.00594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00218 AC: 3192 AN: 1461676 Hom.: 85 Cov.: 31 AF XY: 0.00327 AC XY: 2375 AN XY: 727124

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0351 AC: 3024 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111928

Other (OTH) AF: 0.00212 AC: 128 AN: 60388

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152382 Hom.: 6 Cov.: 33 AF XY: 0.00178 AC XY: 133 AN XY: 74522

African (AFR) AF: 0.0000721 AC: 3 AN: 41598

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0370 AC: 179 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000291

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00472 AC: 573

Asia WGS AF: 0.0170 AC: 61 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	N
PhyloP100		6.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.14
Sift	Benign	0.36	T
Sift4G	Benign	0.68	T
Polyphen		0.0010	B
Vest4		0.22
MVP		0.36
MPC		0.53
ClinPred		0.044	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.10
Mutation Taster		=232/68	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

Other links and lift over

dbSNP: rs201626676; hg19: chr5-169135206;