5-169684341-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_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. 15/21 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 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

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

DOCK2 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

DOCK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK2	NM_004946.3 link	c.752C>T	p.Thr251Met	missense_variant	Exon 8 of 52	ENST00000520908.7	NP_004937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7 link	c.752C>T	p.Thr251Met	missense_variant	Exon 8 of 52	2	NM_004946.3	ENSP00000429283.3

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

GnomAD2 exomes

AF:

0.00924

AC:

2323

AN:

251292

AF XY:

0.00920

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 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

African (AFR)

AF:

0.0243

AC:

813

AN:

33476

American (AMR)

AF:

0.00532

AC:

238

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0344

AC:

898

AN:

26130

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.0160

AC:

1384

AN:

86252

European-Finnish (FIN)

AF:

0.00258

AC:

138

AN:

53394

Middle Eastern (MID)

AF:

0.0208

AC:

120

AN:

5768

European-Non Finnish (NFE)

AF:

0.00762

AC:

8474

AN:

1111952

Other (OTH)

AF:

0.0112

AC:

676

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

675

1349

2024

2698

3373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

360

720

1080

1440

1800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0129

AC:

1959

AN:

152278

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

908

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0247

AC:

1026

AN:

41532

American (AMR)

AF:

0.00738

AC:

113

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0199

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00330

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00800

AC:

544

AN:

68034

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

100

199

299

398

498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0105

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

-0.96

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

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over