rs201626676

Positions:

• chr5-169708202-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 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. 13/20 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

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DOCK2
• 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 id is 476000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-169708202-A-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.1417A>G	p.Met473Val	missense_variant	15/52	ENST00000520908.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.1417A>G	p.Met473Val	missense_variant	15/52	2	NM_004946.3	P1

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

GnomAD3 exomes AF: 0.00432 AC: 1083 AN: 250656 Hom.: 24 AF XY: 0.00594 AC XY: 805 AN XY: 135438

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 SAS exome AF: 0.0349

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

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00212

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

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0370

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000457 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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DOCK2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.72	D
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	N;N
MutationTaster	Benign	0.98	D;D;D
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;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

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: rs201626676; hg19: chr5-169135206;