rs769776739
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_024422.6(DSC2):c.142C>T(p.Leu48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,452,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. L48V) has been classified as Uncertain significance.
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.142C>T | p.Leu48Phe | missense_variant | 2/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.142C>T | p.Leu48Phe | missense_variant | 2/17 | ||
DSC2 | NM_001406506.1 | c.-288C>T | 5_prime_UTR_variant | 2/16 | |||
DSC2 | NM_001406507.1 | c.-288C>T | 5_prime_UTR_variant | 2/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.142C>T | p.Leu48Phe | missense_variant | 2/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.142C>T | p.Leu48Phe | missense_variant | 2/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.-325C>T | 5_prime_UTR_variant | 2/17 | |||||
DSC2 | ENST00000682357.1 | c.-288C>T | 5_prime_UTR_variant | 2/16 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251306Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135824
GnomAD4 exome AF: 0.00000620 AC: 9AN: 1452394Hom.: 0 Cov.: 29 AF XY: 0.00000692 AC XY: 5AN XY: 722738
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 07, 2022 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 410649). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is present in population databases (rs769776739, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 48 of the DSC2 protein (p.Leu48Phe). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2020 | The p.L48F variant (also known as c.142C>T), located in coding exon 2 of the DSC2 gene, results from a C to T substitution at nucleotide position 142. The leucine at codon 48 is replaced by phenylalanine, an amino acid with highly similar properties. 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. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 04, 2019 | - - |
Familial isolated arrhythmogenic right ventricular dysplasia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 31, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at