rs112062072

Positions:

chr5-169803141-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP2BP4_StrongBP6BS1

The NM_004946.3(DOCK2):c.2638C>A(p.Leu880Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,154 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

DOCK2
NM_004946.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.969

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 Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.035981864).

BP6

Variant 5-169803141-C-A is Benign according to our data. Variant chr5-169803141-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542612.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr5-169803141-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000617 (94/152294) while in subpopulation NFE AF= 0.00115 (78/68026). AF 95% confidence interval is 0.000941. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK2	NM_004946.3 linkuse as main transcript	c.2638C>A	p.Leu880Met	missense_variant	26/52	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.2638C>A	p.Leu880Met	missense_variant	26/52	2	NM_004946.3	ENSP00000429283.3		Q92608-1

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000390

AC:

AN:

251282

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000775

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00122

AC:

1784

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

833

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.000617

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000837

Hom.:

Bravo

AF:

0.000665

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DOCK2 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 880 of the DOCK2 protein (p.Leu880Met). This variant is present in population databases (rs112062072, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with DOCK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 542612). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

DOCK2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.5

DANN

Uncertain

0.98

DEOGEN2

Benign

0.049

T;T;.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.52

.;T;T;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.036

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

0.19

N;.;.;N

REVEL

Benign

0.032

Sift

Benign

0.24

T;.;.;T

Sift4G

Benign

0.22

T;.;T;T

Polyphen

0.042

B;B;.;.

Vest4

0.30

MVP

0.36

MPC

0.61

ClinPred

0.015

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.062

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