rs141379407
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024422.6(DSC2):c.266C>T(p.Ser89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,430 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S89S) has been classified as Likely benign.
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.266C>T | p.Ser89Leu | missense_variant | 3/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.266C>T | p.Ser89Leu | missense_variant | 3/17 | ||
DSC2 | NM_001406506.1 | c.-164C>T | 5_prime_UTR_variant | 3/16 | |||
DSC2 | NM_001406507.1 | c.-164C>T | 5_prime_UTR_variant | 3/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.266C>T | p.Ser89Leu | missense_variant | 3/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.266C>T | p.Ser89Leu | missense_variant | 3/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.-201C>T | 5_prime_UTR_variant | 3/17 | |||||
DSC2 | ENST00000682357.1 | c.-164C>T | 5_prime_UTR_variant | 3/16 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152106Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000837 AC: 21AN: 250860Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135580
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461324Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 726962
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152106Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74282
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 20, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 89 of the DSC2 protein (p.Ser89Leu). This variant is present in population databases (rs141379407, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 21859740). ClinVar contains an entry for this variant (Variation ID: 468381). 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) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 30, 2023 | This missense variant replaces serine with leucine at codon 89 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 dilated cardiomyopathy (PMID: 21859740), an individual affected with hypertrophic cardiomyopathy (PMID: 25351510), an infant who died of sudden infant death syndrome (PMID: 27435932), and an individual suspected of having dilated cardiomyopathy (PMID: 30847666). This variant has been identified in 24/282254 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2021 | Has been reported in an individual with dilated cardiomyopathy (Garcia-Pavia et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 468381; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27535533, 21859740) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 23, 2021 | The p.S89L variant (also known as c.266C>T), located in coding exon 3 of the DSC2 gene, results from a C to T substitution at nucleotide position 266. The serine at codon 89 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected in individuals from cohorts with hypertrophic and dilated cardiomyopathy; however, clinical details were limited and, in some cases, additional variants in cardiac-related genes were also detected (Garcia-Pavia P et al. Heart, 2011 Nov;97:1744-52; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Lopes LR et al. J Med Genet, 2013 Apr;50:228-39). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other 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 | Feb 05, 2024 | This missense variant replaces serine with leucine at codon 89 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 dilated cardiomyopathy (PMID: 21859740), an individual affected with hypertrophic cardiomyopathy (PMID: 25351510), an infant who died of sudden infant death syndrome (PMID: 27435932), and an individual suspected of having dilated cardiomyopathy (PMID: 30847666). This variant has been identified in 24/282254 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at