rs1402474064
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024422.6(DSC2):c.2437C>T(p.His813Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
DSC2
NM_024422.6 missense
NM_024422.6 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 4.87
Genes affected
DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22430184).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2437C>T | p.His813Tyr | missense_variant | 15/16 | ENST00000280904.11 | NP_077740.1 | |
DSC2 | NM_004949.5 | c.2437C>T | p.His813Tyr | missense_variant | 15/17 | NP_004940.1 | ||
DSC2 | NM_001406506.1 | c.2008C>T | p.His670Tyr | missense_variant | 15/16 | NP_001393435.1 | ||
DSC2 | NM_001406507.1 | c.2008C>T | p.His670Tyr | missense_variant | 15/17 | NP_001393436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2437C>T | p.His813Tyr | missense_variant | 15/16 | 1 | NM_024422.6 | ENSP00000280904.6 | ||
DSC2 | ENST00000251081.8 | c.2437C>T | p.His813Tyr | missense_variant | 15/17 | 1 | ENSP00000251081.6 | |||
DSC2 | ENST00000648081.1 | c.2008C>T | p.His670Tyr | missense_variant | 16/17 | ENSP00000497441.1 | ||||
DSC2 | ENST00000682357.1 | c.2008C>T | p.His670Tyr | missense_variant | 15/16 | ENSP00000507826.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251246Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135784
GnomAD3 exomes
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461860Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727226
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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1461860
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727226
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 11, 2020 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DSC2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with tyrosine at codon 813 of the DSC2 protein (p.His813Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.
REVEL
Benign
Sift
Benign
T;T;.
Sift4G
Benign
T;T;.
Polyphen
B;B;.
Vest4
MutPred
Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at