rs759775916
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4BS1_Supporting
The NM_004946.3(DOCK2):āc.1349T>Cā(p.Met450Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000837 in 1,613,730 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000039 ( 0 hom., cov: 32)
Exomes š: 0.000088 ( 1 hom. )
Consequence
DOCK2
NM_004946.3 missense
NM_004946.3 missense
Scores
1
9
8
Clinical Significance
Conservation
PhyloP100: 7.99
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DOCK2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.32755718).
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000883 (129/1461568) while in subpopulation MID AF= 0.00156 (9/5764). AF 95% confidence interval is 0.000814. There are 1 homozygotes in gnomad4_exome. There are 71 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOCK2 | NM_004946.3 | c.1349T>C | p.Met450Thr | missense_variant | 14/52 | ENST00000520908.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOCK2 | ENST00000520908.7 | c.1349T>C | p.Met450Thr | missense_variant | 14/52 | 2 | NM_004946.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000956 AC: 24AN: 251034Hom.: 1 AF XY: 0.000140 AC XY: 19AN XY: 135658
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GnomAD4 exome AF: 0.0000883 AC: 129AN: 1461568Hom.: 1 Cov.: 31 AF XY: 0.0000976 AC XY: 71AN XY: 727096
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
DOCK2 deficiency Uncertain:1Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant classified as Uncertain significance and reported on 08-18-2017 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 450 of the DOCK2 protein (p.Met450Thr). This variant is present in population databases (rs759775916, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. 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: 542613). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 28, 2023 | The c.1349T>C (p.M450T) alteration is located in exon 14 (coding exon 14) of the DOCK2 gene. This alteration results from a T to C substitution at nucleotide position 1349, causing the methionine (M) at amino acid position 450 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;D
REVEL
Benign
Sift
Uncertain
D;.;.;D
Sift4G
Uncertain
D;.;.;D
Polyphen
B;B;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at