chr19-38528963-C-CAGG
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP3
The NM_000540.3(RYR1):c.11061_11063dup(p.Glu3688dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0000199 in 1,607,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
RYR1
NM_000540.3 inframe_insertion
NM_000540.3 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.77
Genes affected
RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP3
?
Nonframeshift variant in repetitive region in NM_000540.3
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.11061_11063dup | p.Glu3688dup | inframe_insertion | 76/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.11061_11063dup | p.Glu3688dup | inframe_insertion | 76/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152018Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000230 AC: 5AN: 217000Hom.: 0 AF XY: 0.00000857 AC XY: 1AN XY: 116686
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GnomAD4 exome AF: 0.0000199 AC: 29AN: 1455202Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 12AN XY: 723312
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This variant causes the in-frame insertion of one amino acid in the RYR1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 5/217000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2022 | This variant, c.11061_11063dup, results in the insertion of 1 amino acid(s) of the RYR1 protein (p.Glu3689dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760784102, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at