NM_000540.3:c.7742C>T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_000540.3(RYR1):c.7742C>T(p.Ser2581Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,138 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S2581S) has been classified as Uncertain significance.
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7742C>T | p.Ser2581Phe | missense_variant | Exon 48 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.7742C>T | p.Ser2581Phe | missense_variant | Exon 48 of 105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000594335.5 | n.1193C>T | non_coding_transcript_exon_variant | Exon 9 of 49 | 1 | ENSP00000470927.2 | ||||
RYR1 | ENST00000599547.6 | n.7742C>T | non_coding_transcript_exon_variant | Exon 48 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461138Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2AN XY: 726892
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
not provided Uncertain:2
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The S2581F variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S2581F variant is not observed in large population cohorts (Lek et al., 2016). The S2581F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S2581F as a variant of uncertain significance. -
RYR1-related disorder Uncertain:1
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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 452707). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2581 of the RYR1 protein (p.Ser2581Phe). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at