rs200124278
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_000540.3(RYR1):c.2933C>T(p.Pro978Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P978S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2933C>T | p.Pro978Leu | missense_variant | 24/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2933C>T | p.Pro978Leu | missense_variant | 24/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2933C>T | p.Pro978Leu | missense_variant | 24/105 | 1 | P4 | ||
RYR1 | ENST00000594111.1 | n.26C>T | non_coding_transcript_exon_variant | 1/2 | 2 | ||||
RYR1 | ENST00000599547.6 | c.2933C>T | p.Pro978Leu | missense_variant, NMD_transcript_variant | 24/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000255 AC: 63AN: 247048Hom.: 0 AF XY: 0.000283 AC XY: 38AN XY: 134146
GnomAD4 exome AF: 0.000132 AC: 193AN: 1461086Hom.: 0 Cov.: 30 AF XY: 0.000150 AC XY: 109AN XY: 726858
GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74324
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2017 | The P978L variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P978L variant is observed in 13/5020 alleles (0.259%) alleles from individuals of Finnish background in the ExAC dataset (Lek et al., 2016). The P978L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P978L as a variant of uncertain significance. - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at