rs78243868

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004946.3(DOCK2):​c.752C>A​(p.Thr251Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DOCK2
NM_004946.3 missense

Scores

19

Clinical Significance

Not reported in ClinVar

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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.029485941).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DOCK2NM_004946.3 linkc.752C>A p.Thr251Lys missense_variant Exon 8 of 52 ENST00000520908.7 NP_004937.1 Q92608-1Q5XG91

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DOCK2ENST00000520908.7 linkc.752C>A p.Thr251Lys missense_variant Exon 8 of 52 2 NM_004946.3 ENSP00000429283.3 Q92608-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461780
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
0.024
DANN
Benign
0.44
DEOGEN2
Benign
0.044
T;T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.086
N
LIST_S2
Benign
0.82
.;T
M_CAP
Benign
0.0039
T
MetaRNN
Benign
0.029
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-0.32
N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
1.0
N;.
REVEL
Benign
0.063
Sift
Benign
1.0
T;.
Sift4G
Benign
1.0
T;.
Polyphen
0.14
B;B
Vest4
0.28
MutPred
0.46
Gain of methylation at T251 (P = 0.0043);Gain of methylation at T251 (P = 0.0043);
MVP
0.35
MPC
0.63
ClinPred
0.048
T
GERP RS
-8.5
Varity_R
0.029
gMVP
0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-169111345; API