19-38505906-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_000540.3(RYR1):c.8501C>A(p.Thr2834Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,764 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T2834R) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.8501C>A | p.Thr2834Lys | missense_variant | 54/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.8501C>A | p.Thr2834Lys | missense_variant | 54/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.8501C>A | p.Thr2834Lys | missense_variant | 54/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.1955C>A | p.Thr652Lys | missense_variant, NMD_transcript_variant | 15/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.8501C>A | p.Thr2834Lys | missense_variant, NMD_transcript_variant | 54/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000662 AC: 1AN: 151038Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461726Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727130
GnomAD4 genome AF: 0.00000662 AC: 1AN: 151038Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 73630
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 2834 of the RYR1 protein (p.Thr2834Lys). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at