rs372606274
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4_ModerateBS2
The NM_001943.5(DSG2):c.445G>A(p.Val149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. V149F) has been classified as Uncertain significance.
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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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.445G>A | p.Val149Ile | missense_variant | 5/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.-90G>A | 5_prime_UTR_variant | 6/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.445G>A | p.Val149Ile | missense_variant | 5/15 | 1 | NM_001943.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151944Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249368Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135276
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461766Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727182
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152052Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74326
ClinVar
Submissions by phenotype
not provided Uncertain:3
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 | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 14, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces valine with isoleucine at codon 149 of the DSG2 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24704780). This variant has been identified in 8/280720 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 01, 2022 | This missense variant replaces valine with isoleucine at codon 149 of the DSG2 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24704780). This variant has been identified in 8/280720 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 | Oct 31, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 149 of the DSG2 protein (p.Val149Ile). This variant is present in population databases (rs372606274, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 24704780, 32880476, 34012299). ClinVar contains an entry for this variant (Variation ID: 218601). 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. 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 | Aug 04, 2021 | The p.V149I variant (also known as c.445G>A), located in coding exon 5 of the DSG2 gene, results from a G to A substitution at nucleotide position 445. The valine at codon 149 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in a family (who also had variants in other cardiac-related genes) from a cohort with definite or possible arrhythmogenic right ventricular cardiomyopathy (ARVC), and also co-occurred with a variant in the DSC2 gene in an individual from a dilated cardiomyopathy cohort; however, clinical details were limited (Rasmussen TB et al. Circ Cardiovasc Genet, 2014 Jun;7:230-40; Verdonschot JAJ et al. Circ Genom Precis Med. 2020 10;13(5):476-487). This variant has also been detected in an individual reported to have ARVC, and was also present in two unaffected relatives (Huang R et al. Int Med Case Rep J. 2021 May;14:307-313). This amino acid position is highly 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at