chr19-38507816-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000540.3(RYR1):āc.8921T>Cā(p.Ile2974Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000404 in 1,610,494 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 ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2974V) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.8921T>C | p.Ile2974Thr | missense_variant | 58/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.8921T>C | p.Ile2974Thr | missense_variant | 58/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.8921T>C | p.Ile2974Thr | missense_variant | 58/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.2375T>C | p.Ile792Thr | missense_variant, NMD_transcript_variant | 19/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.8921T>C | p.Ile2974Thr | missense_variant, NMD_transcript_variant | 58/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151710Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251480Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 0.0000425 AC: 62AN: 1458784Hom.: 0 Cov.: 30 AF XY: 0.0000386 AC XY: 28AN XY: 725912
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151710Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74052
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2974 of the RYR1 protein (p.Ile2974Thr). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 579577). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. 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. - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 29, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at