rs111976711
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_000540.3(RYR1):c.2680C>A(p.Pro894Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,611,862 control chromosomes in the GnomAD database, including 3 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P894L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense, splice_region
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 |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2680C>A | p.Pro894Thr | missense_variant, splice_region_variant | 21/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2680C>A | p.Pro894Thr | missense_variant, splice_region_variant | 21/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2680C>A | p.Pro894Thr | missense_variant, splice_region_variant | 21/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2680C>A | p.Pro894Thr | missense_variant, splice_region_variant, NMD_transcript_variant | 21/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000406 AC: 1AN: 246418Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133910
GnomAD4 exome AF: 0.0000343 AC: 50AN: 1459544Hom.: 3 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 726144
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152318Hom.: 0 Cov.: 30 AF XY: 0.0000537 AC XY: 4AN XY: 74480
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 894 of the RYR1 protein (p.Pro894Thr). This variant is not present in population databases (gnomAD no frequency). 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: 478217). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at