18-31524751-A-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001943.5(DSG2):c.877A>T(p.Ile293Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I293V) has been classified as Benign.
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.877A>T | p.Ile293Leu | missense_variant | 8/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.343A>T | p.Ile115Leu | missense_variant | 9/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.877A>T | p.Ile293Leu | missense_variant | 8/15 | 1 | NM_001943.5 | P1 | |
DSG2 | ENST00000682087.2 | n.708A>T | non_coding_transcript_exon_variant | 6/6 | |||||
DSG2 | ENST00000683614.2 | n.708A>T | non_coding_transcript_exon_variant | 6/7 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249370Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135304
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461862Hom.: 0 Cov.: 37 AF XY: 0.0000578 AC XY: 42AN XY: 727230
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74368
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2016 | Variant summary: The DSG2 c.877A>T (p.Ile293Leu) variant causes a missense change involving a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/120730 (1/60365), which exceeds the estimated maximal expected allele frequency for a pathogenic DSG2 variant of 1/100000, however, this observation needs to be cautiously considered due to the cohort potentially harboring phenotypes that could be caused by a DSG2 mutation. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although a clinical laboratory cites the variant as "likely benign," without additional information for an independent evaluation. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces isoleucine with leucine at codon 293 of the DSG2 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/280772 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2023 | This missense variant replaces isoleucine with leucine at codon 293 of the DSG2 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/280772 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. - |
Arrhythmogenic right ventricular dysplasia 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 293 of the DSG2 protein (p.Ile293Leu). This variant is present in population databases (rs2230234, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 36014). 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 DSG2 protein function with a negative predictive value of 95%. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 30, 2021 | The c.877A>T (p.I293L) alteration is located in exon 8 (coding exon 8) of the DSG2 gene. This alteration results from a A to T substitution at nucleotide position 877, causing the isoleucine (I) at amino acid position 293 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at