chr5-169684341-C-T

Position:

chr5-169684341-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_004946.3(DOCK2):c.752C>T(p.Thr251Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00911 in 1,614,052 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T251T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 91 hom. )

Consequence

DOCK2
NM_004946.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.961

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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=0.002072692).

BP6

Variant 5-169684341-C-T is Benign according to our data. Variant chr5-169684341-C-T is described in ClinVar as [Benign]. Clinvar id is 476018.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1959/152278) while in subpopulation AFR AF= 0.0247 (1026/41532). AF 95% confidence interval is 0.0234. There are 23 homozygotes in gnomad4. There are 908 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3 linkuse as main transcript	c.752C>T	p.Thr251Met	missense_variant	8/52	ENST00000520908.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7 linkuse as main transcript	c.752C>T	p.Thr251Met	missense_variant	8/52	2	NM_004946.3	P1	Q92608-1
DOCK2	ENST00000524185.5 linkuse as main transcript	c.752C>T	p.Thr251Met	missense_variant, NMD_transcript_variant	8/53	1
DOCK2	ENST00000519628.2 linkuse as main transcript	c.752C>T	p.Thr251Met	missense_variant	8/28	3
DOCK2	ENST00000522138.2 linkuse as main transcript	c.*262C>T		3_prime_UTR_variant, NMD_transcript_variant	8/52	3

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1958

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0201

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00800

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00924

AC:

2323

AN:

251292

Hom.:

AF XY:

0.00920

AC XY:

1249

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.0249

Gnomad AMR exome

AF:

0.00477

Gnomad ASJ exome

AF:

0.0325

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0151

Gnomad FIN exome

AF:

0.00277

Gnomad NFE exome

AF:

0.00731

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.00872

AC:

12745

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00894

AC XY:

6500

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0243

Gnomad4 AMR exome

AF:

0.00532

Gnomad4 ASJ exome

AF:

0.0344

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0160

Gnomad4 FIN exome

AF:

0.00258

Gnomad4 NFE exome

AF:

0.00762

Gnomad4 OTH exome

AF:

0.0112

GnomAD4 genome

AF:

0.0129

AC:

1959

AN:

152278

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

908

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0247

Gnomad4 AMR

AF:

0.00738

Gnomad4 ASJ

AF:

0.0349

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.00800

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00995

Hom.:

Bravo

AF:

0.0133

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00913

AC:

1108

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.00931

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

DOCK2 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.2

DANN

Benign

0.91

DEOGEN2

Benign

0.096

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.69

.;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.96

N;.

REVEL

Benign

0.045

Sift

Benign

0.15

T;.

Sift4G

Benign

0.10

T;.

Polyphen

0.0050

B;B

Vest4

0.16

MVP

0.32

MPC

0.54

ClinPred

0.0017

GERP RS

-8.5

Varity_R

0.013

gMVP

0.22

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