rs202031070
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_024422.6(DSC2):c.2591C>T(p.Ser864Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S864A) has been classified as Uncertain significance.
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2591C>T | p.Ser864Leu | missense_variant | 16/16 | ENST00000280904.11 | |
DSC2 | NM_001406506.1 | c.2162C>T | p.Ser721Leu | missense_variant | 16/16 | ||
DSC2 | NM_001406507.1 | c.*93C>T | 3_prime_UTR_variant | 17/17 | |||
DSC2 | NM_004949.5 | c.*93C>T | 3_prime_UTR_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2591C>T | p.Ser864Leu | missense_variant | 16/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.*93C>T | 3_prime_UTR_variant | 17/17 | 1 | ||||
DSC2 | ENST00000648081.1 | c.2162C>T | p.Ser721Leu | missense_variant | 17/17 | ||||
DSC2 | ENST00000682357.1 | c.2162C>T | p.Ser721Leu | missense_variant | 16/16 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152052Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251026Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135654
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461792Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727186
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74388
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 20, 2022 | This missense variant replaces serine with leucine at codon 864 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 22, 2023 | - - |
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2022 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 864 of the DSC2 protein (p.Ser864Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 536272). 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 disruptive. 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. - |
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 | Dec 01, 2023 | This missense variant replaces serine with leucine at codon 864 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at