rs139290300
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_024422.6(DSC2):c.2335G>A(p.Gly779Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
DSC2
NM_024422.6 missense
NM_024422.6 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 1.91
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 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.28969115).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2335G>A | p.Gly779Arg | missense_variant | 15/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.2335G>A | p.Gly779Arg | missense_variant | 15/17 | ||
DSC2 | NM_001406506.1 | c.1906G>A | p.Gly636Arg | missense_variant | 15/16 | ||
DSC2 | NM_001406507.1 | c.1906G>A | p.Gly636Arg | missense_variant | 15/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2335G>A | p.Gly779Arg | missense_variant | 15/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.2335G>A | p.Gly779Arg | missense_variant | 15/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.1906G>A | p.Gly636Arg | missense_variant | 16/17 | ||||
DSC2 | ENST00000682357.1 | c.1906G>A | p.Gly636Arg | missense_variant | 15/16 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251112Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135706
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GnomAD4 exome AF: 0.000108 AC: 158AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000990 AC XY: 72AN XY: 727228
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2014 | p.Gly779Arg (GGA>AGA): c.2335 G>A in exon 15 of the DSC2 gene (NM_024422.3) A variant of unknown significance has been identified in the DSC2 gene. The G779R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G779R variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G779R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, mutations in nearby residues have not been reported in association with arrhythmia, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 05, 2016 | - - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 779 of the DSC2 protein (p.Gly779Arg). This variant is present in population databases (rs139290300, gnomAD 0.009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 25351510, 31737537). ClinVar contains an entry for this variant (Variation ID: 191619). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSC2 protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 09, 2022 | This missense variant replaces glycine with arginine at codon 779 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 11/282502 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces glycine with arginine at codon 779 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 11/282502 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
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
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;.
REVEL
Benign
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Gain of solvent accessibility (P = 2e-04);Gain of solvent accessibility (P = 2e-04);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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