5-169702332-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004946.3(DOCK2):​c.1288C>G​(p.Leu430Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DOCK2
NM_004946.3 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:2

Conservation

PhyloP100: 1.19

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2358166).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DOCK2NM_004946.3 linkc.1288C>G p.Leu430Val missense_variant Exon 14 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.1288C>G p.Leu430Val missense_variant Exon 14 of 52 2 NM_004946.3 ENSP00000429283.3 Q92608-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000159
AC:
4
AN:
250962
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461670
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
AN XY:
727142
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39678
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000288
AC:
32
AN:
1111862
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000394
AC:
6
AN:
152160
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74334
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41434
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000882
AC:
6
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000838
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

DOCK2 deficiency Uncertain:1Other:2
-
GenomeConnect, ClinGen
Significance:not provided
Review Status:no classification provided
Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jun 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 430 of the DOCK2 protein (p.Leu430Val). This variant is present in population databases (rs370264550, gnomAD 0.005%). 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: 542615). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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. -

-
GenomeConnect - Invitae Patient Insights Network
Significance:not provided
Review Status:no classification provided
Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 04-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Inborn genetic diseases Uncertain:1
Jun 07, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1288C>G (p.L430V) alteration is located in exon 14 (coding exon 14) of the DOCK2 gene. This alteration results from a C to G substitution at nucleotide position 1288, causing the leucine (L) at amino acid position 430 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;T;.
Eigen
Benign
-0.097
Eigen_PC
Benign
0.0043
FATHMM_MKL
Benign
0.62
D
LIST_S2
Pathogenic
0.98
.;D;D
M_CAP
Benign
0.0074
T
MetaRNN
Benign
0.24
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.7
M;M;.
PhyloP100
1.2
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-2.2
N;.;.
REVEL
Benign
0.16
Sift
Benign
0.058
T;.;.
Sift4G
Uncertain
0.049
D;.;.
Polyphen
0.060
B;B;.
Vest4
0.63
MVP
0.58
MPC
0.82
ClinPred
0.26
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.27
gMVP
0.63
Mutation Taster
=78/22
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs370264550; hg19: chr5-169129336; API