rs114888195

Positions:

chr5-169702404-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_004946.3(DOCK2):c.1360G>A(p.Ala454Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,613,862 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 3 hom. )

Consequence

DOCK2
NM_004946.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.02

Variant links:

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 links:

DOCK2 (HGNC:):

DOCK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DOCK2. . Trascript score misZ 4.9036 (greater than threshold 3.09). GenCC has associacion of gene with DOCK2 deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.008157015).

BP6

Variant 5-169702404-G-A is Benign according to our data. Variant chr5-169702404-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475999.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00193 (294/152260) while in subpopulation AFR AF= 0.00676 (281/41544). AF 95% confidence interval is 0.00611. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK2	NM_004946.3 linkuse as main transcript	c.1360G>A	p.Ala454Thr	missense_variant	14/52	ENST00000520908.7	NP_004937.1	Q92608-1Q5XG91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7 linkuse as main transcript	c.1360G>A	p.Ala454Thr	missense_variant	14/52	2	NM_004946.3	ENSP00000429283.3		Q92608-1

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00678

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000534

AC:

134

AN:

250952

Hom.:

AF XY:

0.000428

AC XY:

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.00677

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000248

AC:

363

AN:

1461602

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00765

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00113

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00193

AC:

294

AN:

152260

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00676

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000355

Hom.:

Bravo

AF:

0.00209

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000626

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DOCK2 deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

DOCK2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.1

DANN

Benign

0.93

DEOGEN2

Benign

0.046

T;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.72

.;T;T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.0082

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.34

N;N;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

0.96

N;.;.;.

REVEL

Benign

0.063

Sift

Benign

0.19

T;.;.;.

Sift4G

Benign

0.094

T;.;.;T

Polyphen

0.0

B;B;.;.

Vest4

0.057

MVP

0.11

MPC

0.50

ClinPred

0.0078

GERP RS

-0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over