chr19-38467812-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7
The NM_000540.3(RYR1):c.3381C>T(p.Arg1127Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000540.3 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.3381C>T | p.Arg1127Arg | splice_region_variant, synonymous_variant | Exon 25 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.3381C>T | p.Arg1127Arg | splice_region_variant, synonymous_variant | Exon 25 of 105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000594111.1 | n.474C>T | non_coding_transcript_exon_variant | Exon 2 of 2 | 2 | |||||
RYR1 | ENST00000599547.6 | n.3381C>T | splice_region_variant, non_coding_transcript_exon_variant | Exon 25 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes AF: 0.000283 AC: 43AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000260 AC: 65AN: 249884Hom.: 1 AF XY: 0.000266 AC XY: 36AN XY: 135224
GnomAD4 exome AF: 0.000121 AC: 177AN: 1461530Hom.: 1 Cov.: 31 AF XY: 0.000120 AC XY: 87AN XY: 727070
GnomAD4 genome AF: 0.000276 AC: 42AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74468
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
RYR1: BP4, BP7 -
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Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27535533) -
RYR1-related disorder Uncertain:1
This sequence change affects codon 1127 of the RYR1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RYR1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200780880, gnomAD 0.06%). 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: 256491). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -
not specified Benign:1
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Malignant hyperthermia, susceptibility to, 1 Benign:1
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Malignant hyperthermia of anesthesia Benign:1
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Multiminicore myopathy Benign:1
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Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1
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Central core myopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at