rs567084532
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS2
The NM_000540.3(RYR1):āc.1909A>Gā(p.Ile637Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,134 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I637I) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.1909A>G | p.Ile637Val | missense_variant | 17/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.1909A>G | p.Ile637Val | missense_variant | 17/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.1909A>G | p.Ile637Val | missense_variant | 17/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.1909A>G | p.Ile637Val | missense_variant, NMD_transcript_variant | 17/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152122Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000215 AC: 54AN: 251488Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135918
GnomAD4 exome AF: 0.0000882 AC: 129AN: 1461894Hom.: 4 Cov.: 33 AF XY: 0.0000908 AC XY: 66AN XY: 727248
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152240Hom.: 0 Cov.: 30 AF XY: 0.0000672 AC XY: 5AN XY: 74452
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 23, 2023 | The RYR1 c.1909A>G variant is predicted to result in the amino acid substitution p.Ile637Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.16% of alleles in individuals of South Asian descent in gnomAD, which is likely too common to be a primary cause of autosomal dominant disorders (http://gnomad.broadinstitute.org/variant/19-38948254-A-G). Although we suspect that this variant may be benign, 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 | GeneDx | Mar 27, 2017 | The I637V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I637V variant is observed in 37/16512 (0.22%) alleles from individuals of South Asian background, including 1 homozygous individual in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at