chr19-38566950-C-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_000540.3(RYR1):āc.13477C>Gā(p.Pro4493Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,606,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. P4493S) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.13477C>G | p.Pro4493Ala | missense_variant | 92/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.13477C>G | p.Pro4493Ala | missense_variant | 92/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000210 AC: 32AN: 152144Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000222 AC: 52AN: 234482Hom.: 0 AF XY: 0.000213 AC XY: 27AN XY: 126984
GnomAD4 exome AF: 0.000281 AC: 409AN: 1454062Hom.: 0 Cov.: 32 AF XY: 0.000273 AC XY: 197AN XY: 722496
GnomAD4 genome AF: 0.000210 AC: 32AN: 152144Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15AN XY: 74326
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2021 | Reported in a patient with myalgia and muscle biopsy showing multiminicores in published literature (Duarte et al., 2011); second variant (c.14505 G>A) reported in this individual is classified as likely benign at GeneDx; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21674524) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 22, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2016 | - - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;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 | Oct 31, 2018 | - - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at