rs140197877
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP7BS1BP4
This summary comes from the ClinGen Evidence Repository: The c.9093C>T (p.Ala3031=) variant (NM_000540.3(RYR1):c.9093C>T (p.Ala3031=)) in RYR1 is a synonymous (silent) variant that is not predicted by Splice AI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC genome browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 3/6084) of the c.9093C>T variant in RYR1 is 0.0001414 for Middle Eastern chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000006) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for RYR1-related myopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1, BP4, BP7 (Congenital Myopathies VCEP Specifications Version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA073137/MONDO:0100150/179
Frequency
Consequence
NM_000540.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.9093C>T | p.Ala3031= | synonymous_variant | 60/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.9093C>T | p.Ala3031= | synonymous_variant | 60/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.9093C>T | p.Ala3031= | synonymous_variant | 60/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.2547C>T | p.Ala849= | synonymous_variant, NMD_transcript_variant | 21/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.9093C>T | p.Ala3031= | synonymous_variant, NMD_transcript_variant | 60/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251492Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135920
GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 727246
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74340
ClinVar
Submissions by phenotype
RYR1-related disorder Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 12, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | - - |
Central core myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Malignant hyperthermia, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Malignant hyperthermia of anesthesia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | RYR1: BP4, BP7 - |
Multiminicore myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at