rs199918720
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000280904.11(DSC2):āc.854T>Cā(p.Ile285Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000743 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I285V) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000280904.11 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.854T>C | p.Ile285Thr | missense_variant | 7/16 | ENST00000280904.11 | NP_077740.1 | |
DSC2 | NM_004949.5 | c.854T>C | p.Ile285Thr | missense_variant | 7/17 | NP_004940.1 | ||
DSC2 | NM_001406506.1 | c.425T>C | p.Ile142Thr | missense_variant | 7/16 | NP_001393435.1 | ||
DSC2 | NM_001406507.1 | c.425T>C | p.Ile142Thr | missense_variant | 7/17 | NP_001393436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.854T>C | p.Ile285Thr | missense_variant | 7/16 | 1 | NM_024422.6 | ENSP00000280904 | P1 | |
DSC2 | ENST00000251081.8 | c.854T>C | p.Ile285Thr | missense_variant | 7/17 | 1 | ENSP00000251081 | |||
DSC2 | ENST00000648081.1 | c.425T>C | p.Ile142Thr | missense_variant | 8/17 | ENSP00000497441 | ||||
DSC2 | ENST00000682357.1 | c.425T>C | p.Ile142Thr | missense_variant | 7/16 | ENSP00000507826 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251358Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135850
GnomAD4 exome AF: 0.0000609 AC: 89AN: 1461824Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727210
GnomAD4 genome AF: 0.000204 AC: 31AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 10, 2017 | The I285T variant of uncertain significance in the DSC2 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external variant database. However, the Exome Aggregation Consortium (ExAC) reports I285T was observed in approximately 0.2% of alleles from individuals of European (Finnish) background, indicating it may be a rare variant in this population. Nevertheless, the I285T 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 within the extracellular cadherin 2 domain where only amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 20, 2018 | The DSC2 c.854T>C; p.Ile285Thr variant (rs199918720), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 326398). This variant is found in the Finnish European population with an overall allele frequency of 0.13% (34/ 25786 alleles) in the Genome Aggregation Database. The isoleucine at codon 285 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ile285Thr variant is uncertain at this time. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 30, 2023 | This missense variant replaces isoleucine with threonine at codon 285 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) and in individuals suspected of having noncompaction cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant occurs at an appreciable frequency in the general population and has been identified in 40/282762 chromosomes ((33/25085 Finnish European chromosomes) 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2023 | The p.I285T variant (also known as c.854T>C), located in coding exon 7 of the DSC2 gene, results from a T to C substitution at nucleotide position 854. The isoleucine at codon 285 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and cardiomyopathy genetic testing cohorts; however, clinical details were limited and additional cardiac variants were detected in some cases (Lopes LR et al. Heart, 2015 Feb;101:294-301; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 | Sep 23, 2024 | This missense variant replaces isoleucine with threonine at codon 285 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) and in individuals suspected of having noncompaction cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant occurs at an appreciable frequency in the general population and has been identified in 40/282762 chromosomes ((33/25085 Finnish European chromosomes) 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at