rs995399684
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_000540.3(RYR1):c.12886C>T(p.Arg4296Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 990,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. R4296P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.12886C>T | p.Arg4296Trp | missense_variant | 91/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.12886C>T | p.Arg4296Trp | missense_variant | 91/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000363 AC: 53AN: 145950Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00490 AC: 1AN: 204Hom.: 0 AF XY: 0.00862 AC XY: 1AN XY: 116
GnomAD4 exome AF: 0.000322 AC: 272AN: 844026Hom.: 0 Cov.: 30 AF XY: 0.000309 AC XY: 121AN XY: 391094
GnomAD4 genome ? AF: 0.000377 AC: 55AN: 146056Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 21AN XY: 71088
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 20, 2023 | The RYR1 c.12886C>T (p.Arg4296Trp) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. The highest frequency of this allele in the Genome Aggregation Database is 0.000641 in the African/African American population (version 3.1.2). This frequency is high for autosomal dominant inheritance but may be consistent with autosomal recessive inheritance. Based on the available evidence, the c.12886C>T (p.Arg4296Trp) variant is classified as a variant of uncertain significance for RYR1-related disorders. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4296 of the RYR1 protein (p.Arg4296Trp). This variant is present in population databases (no rsID available, gnomAD 50%). 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: 521376). 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. 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20681998) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2016 | - - |
Central core myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 12, 2022 | - - |
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 | Jul 26, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at