18-31091094-T-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2
The NM_024422.6(DSC2):āc.408A>Gā(p.Arg136Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,066 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024422.6 synonymous
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.408A>G | p.Arg136Arg | synonymous_variant | Exon 4 of 16 | ENST00000280904.11 | NP_077740.1 | |
DSC2 | NM_004949.5 | c.408A>G | p.Arg136Arg | synonymous_variant | Exon 4 of 17 | NP_004940.1 | ||
DSC2 | NM_001406506.1 | c.-22A>G | 5_prime_UTR_variant | Exon 4 of 16 | NP_001393435.1 | |||
DSC2 | NM_001406507.1 | c.-22A>G | 5_prime_UTR_variant | Exon 4 of 17 | NP_001393436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.408A>G | p.Arg136Arg | synonymous_variant | Exon 4 of 16 | 1 | NM_024422.6 | ENSP00000280904.6 | ||
DSC2 | ENST00000251081.8 | c.408A>G | p.Arg136Arg | synonymous_variant | Exon 4 of 17 | 1 | ENSP00000251081.6 | |||
DSC2 | ENST00000648081.1 | c.-22A>G | 5_prime_UTR_variant | Exon 5 of 17 | ENSP00000497441.1 | |||||
DSC2 | ENST00000682357.1 | c.-22A>G | 5_prime_UTR_variant | Exon 4 of 16 | ENSP00000507826.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251304Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135822
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461776Hom.: 2 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727194
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74476
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: DSC2 c.408A>G alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic exonic 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251304 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (4.4e-05 vs 0.00016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.408A>G in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3, likely benign, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This variant is located in exon 4 (of 16 exons) does not change the amino acid at codon 136, however BDGP and ESEfinder splice prediction tools predict this alteration to create an alternate donor splice site. There is no direct function evidence available. The arginine at codon 136 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 136 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 11/22/13). Note that this dataset does not match the patient's ancestry (Asian). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 11/22/13). -
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1Benign:1
- -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Cardiomyopathy Benign:1
- -
Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Familial isolated arrhythmogenic right ventricular dysplasia Benign:1
This synonymous variant does not change the amino acid sequence of the DSC2 protein. However, splice prediction tools suggest that this variant may disrupt RNA splicing. To our knowledge, functional studies have not been performed to investigate this prediction. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/251304 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