chr19-38463761-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_000540.3(RYR1):c.2697C>A(p.Asn899Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2697C>A | p.Asn899Lys | missense_variant | 22/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2697C>A | p.Asn899Lys | missense_variant | 22/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2697C>A | p.Asn899Lys | missense_variant | 22/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2697C>A | p.Asn899Lys | missense_variant, NMD_transcript_variant | 22/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152132Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251490Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135920
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727238
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152132Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74304
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 899 of the RYR1 protein (p.Asn899Lys). This variant is present in population databases (rs201401814, gnomAD 0.04%). This missense change has been observed in individual(s) with idiopathic hyperCKemia and equivocal in vitro contracture test result with halothane and a negative personal and family history for malignant hyperthermia (PMID: 20681998, 24195946). ClinVar contains an entry for this variant (Variation ID: 224375). 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. - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 24, 2021 | - - |
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 12, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at