chr18-31080180-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024422.6(DSC2):c.1436G>A(p.Arg479His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. R479L) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.1436G>A | p.Arg479His | missense_variant | 10/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.1436G>A | p.Arg479His | missense_variant | 10/17 | ||
DSC2 | NM_001406506.1 | c.1007G>A | p.Arg336His | missense_variant | 10/16 | ||
DSC2 | NM_001406507.1 | c.1007G>A | p.Arg336His | missense_variant | 10/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.1436G>A | p.Arg479His | missense_variant | 10/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.1436G>A | p.Arg479His | missense_variant | 10/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.1007G>A | p.Arg336His | missense_variant | 11/17 | ||||
DSC2 | ENST00000682357.1 | c.1007G>A | p.Arg336His | missense_variant | 10/16 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251214Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135774
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461824Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727210
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 29, 2021 | - - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 30, 2021 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 479 of the DSC2 protein (p.Arg479His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410647). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 | Nov 02, 2021 | The c.1436G>A (p.R479H) alteration is located in exon 10 (coding exon 10) of the DSC2 gene. This alteration results from a G to A substitution at nucleotide position 1436, causing the arginine (R) at amino acid position 479 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | This missense variant replaces arginine with histidine at codon 479 of the DSC2 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 DSC2-related disorders in the literature. This variant has been identified in 1/251214 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at