rs1292252892
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_000540.3(RYR1):āc.7661T>Cā(p.Leu2554Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Synonymous variant affecting the same amino acid position (i.e. L2554L) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7661T>C | p.Leu2554Pro | missense_variant | 48/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7661T>C | p.Leu2554Pro | missense_variant | 48/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7661T>C | p.Leu2554Pro | missense_variant | 48/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.1115T>C | p.Leu372Pro | missense_variant, NMD_transcript_variant | 9/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7661T>C | p.Leu2554Pro | missense_variant, NMD_transcript_variant | 48/80 | 2 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249266Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135116
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459478Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 726106
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | 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. 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 C0"). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2554 of the RYR1 protein (p.Leu2554Pro). 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: 478274). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at