rs2229142
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_000540.3(RYR1):āc.7863C>Gā(p.His2621Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,128 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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2621Y) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7863C>G | p.His2621Gln | missense_variant | 49/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7863C>G | p.His2621Gln | missense_variant | 49/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7863C>G | p.His2621Gln | missense_variant | 49/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.1317C>G | p.His439Gln | missense_variant, NMD_transcript_variant | 10/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7863C>G | p.His2621Gln | missense_variant, NMD_transcript_variant | 49/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459128Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1AN XY: 725960
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 29, 2022 | 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. This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2621 of the RYR1 protein (p.His2621Gln). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at