rs397517400
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_024422.6(DSC2):c.474+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024422.6 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.474+5C>T | splice_donor_5th_base_variant, intron_variant | ENST00000280904.11 | |||
DSC2 | NM_001406506.1 | c.45+5C>T | splice_donor_5th_base_variant, intron_variant | ||||
DSC2 | NM_001406507.1 | c.45+5C>T | splice_donor_5th_base_variant, intron_variant | ||||
DSC2 | NM_004949.5 | c.474+5C>T | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.474+5C>T | splice_donor_5th_base_variant, intron_variant | 1 | NM_024422.6 | P1 | |||
DSC2 | ENST00000251081.8 | c.474+5C>T | splice_donor_5th_base_variant, intron_variant | 1 | |||||
DSC2 | ENST00000648081.1 | c.45+5C>T | splice_donor_5th_base_variant, intron_variant | ||||||
DSC2 | ENST00000682357.1 | c.45+5C>T | splice_donor_5th_base_variant, intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251206Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135758
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461648Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727114
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74296
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 20, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2018 | - - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2020 | This sequence change falls in intron 4 of the DSC2 gene. It does not directly change the encoded amino acid sequence of the DSC2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs397517400, ExAC 0.009%). This variant has not been reported in the literature in individuals with DSC2-related disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2022 | This alteration is classified as likely 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
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at