rs915888072
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_024422.6(DSC2):c.1781T>C(p.Ile594Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I594V) has been classified as Uncertain significance.
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.1781T>C | p.Ile594Thr | missense_variant | 12/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.1781T>C | p.Ile594Thr | missense_variant | 12/17 | ||
DSC2 | NM_001406506.1 | c.1352T>C | p.Ile451Thr | missense_variant | 12/16 | ||
DSC2 | NM_001406507.1 | c.1352T>C | p.Ile451Thr | missense_variant | 12/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.1781T>C | p.Ile594Thr | missense_variant | 12/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.1781T>C | p.Ile594Thr | missense_variant | 12/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.1352T>C | p.Ile451Thr | missense_variant | 13/17 | ||||
DSC2 | ENST00000682357.1 | c.1352T>C | p.Ile451Thr | missense_variant | 12/16 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251068Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135692
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461794Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727192
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces isoleucine with threonine at codon 594 of the DSC2 protein (p.Ile594Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | - | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2023 | The c.1781T>C (p.I594T) alteration is located in exon 12 (coding exon 12) of the DSC2 gene. This alteration results from a T to C substitution at nucleotide position 1781, causing the isoleucine (I) at amino acid position 594 to be replaced by a threonine (T). 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