19-38510524-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_000540.3(RYR1):āc.8959G>Cā(p.Glu2987Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,614,032 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2987G) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.8959G>C | p.Glu2987Gln | missense_variant | 59/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.8959G>C | p.Glu2987Gln | missense_variant | 59/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.8959G>C | p.Glu2987Gln | missense_variant | 59/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.2413G>C | p.Glu805Gln | missense_variant, NMD_transcript_variant | 20/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.8959G>C | p.Glu2987Gln | missense_variant, NMD_transcript_variant | 59/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152144Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000596 AC: 15AN: 251488Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135922
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727242
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152144Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74324
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 2987 of the RYR1 protein (p.Glu2987Gln). This variant is present in population databases (rs368065870, gnomAD 0.01%). 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: 590622). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2024 | The RYR1 c.8959G>C variant is predicted to result in the amino acid substitution p.Glu2987Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 18, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at