rs587784374
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000540.3(RYR1):c.3801delC(p.Cys1268AlafsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000540.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.3801delC | p.Cys1268AlafsTer4 | frameshift_variant | Exon 28 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.3801delC | p.Cys1268AlafsTer4 | frameshift_variant | Exon 28 of 105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000599547.6 | n.3801delC | non_coding_transcript_exon_variant | Exon 28 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248410Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134726
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461516Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727106
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
RYR1-related disorder Pathogenic:1
This sequence change creates a premature translational stop signal (p.Cys1268Alafs*4) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1986505). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at