rs201375572
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_000540.3(RYR1):c.7482C>G(p.Phe2494Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000875 in 1,600,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F2494F) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7482C>G | p.Phe2494Leu | missense_variant | 47/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7482C>G | p.Phe2494Leu | missense_variant | 47/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7482C>G | p.Phe2494Leu | missense_variant | 47/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.936C>G | p.Phe312Leu | missense_variant, NMD_transcript_variant | 8/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7482C>G | p.Phe2494Leu | missense_variant, NMD_transcript_variant | 47/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000661 AC: 1AN: 151296Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251336Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135890
GnomAD4 exome AF: 0.00000897 AC: 13AN: 1449156Hom.: 0 Cov.: 49 AF XY: 0.0000153 AC XY: 11AN XY: 720622
GnomAD4 genome ? AF: 0.00000661 AC: 1AN: 151296Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 73872
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 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. 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 not expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 1008302). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is present in population databases (rs201375572, gnomAD 0.02%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2494 of the RYR1 protein (p.Phe2494Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at