rs397516705
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001943.5(DSG2):c.2212G>A(p.Ala738Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. A738A) has been classified as Likely benign.
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.2212G>A | p.Ala738Thr | missense_variant | 14/15 | ENST00000261590.13 | |
DSG2-AS1 | NR_045216.1 | n.1810+372C>T | intron_variant, non_coding_transcript_variant | ||||
DSG2 | XM_047437315.1 | c.1678G>A | p.Ala560Thr | missense_variant | 15/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.2212G>A | p.Ala738Thr | missense_variant | 14/15 | 1 | NM_001943.5 | P1 | |
DSG2-AS1 | ENST00000583706.5 | n.1848+372C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249418Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135298
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727248
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74334
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 03, 2023 | The p.Ala738Thr variant in DSG2 has been reported in 2 individuals with arrhythmogenic right ventricular cardiomyopathy, including 1 individual who had another pathogenic ARVC-associated variant that is considered sufficient to cause disease (ARVC; Stava 2022 PMID: 35653365, LMM data), in 1 individual with Brugada Syndrome (Di Resta 2015 PMID: 26220970) and by other clinical laboratories in ClinVar (Variation ID 44298). It has also been identified in 0.003% (2/68030) of European chromosomes by gnomAD (https://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign . ACMG/AMP Criteria applied: PM2_Supporting, BP4. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This missense variant replaces alanine with threonine at codon 738 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 4/249418 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 | Jun 07, 2023 | This missense variant replaces alanine with threonine at codon 738 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 been reported in an individual affected Brugada syndrome (PMID: 26220970). This variant has been identified in 4/249418 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 | Nov 28, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 738 of the DSG2 protein (p.Ala738Thr). This variant is present in population databases (rs397516705, gnomAD 0.007%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 44298). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at