rs745619519
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7
The NM_000540.3(RYR1):c.8082G>A(p.Glu2694Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,050 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
RYR1
NM_000540.3 synonymous
NM_000540.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.11
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 -4 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 19-38504762-G-A is Benign according to our data. Variant chr19-38504762-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329076.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
BP7
Synonymous conserved (PhyloP=1.12 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.8082G>A | p.Glu2694Glu | synonymous_variant | 51/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.8082G>A | p.Glu2694Glu | synonymous_variant | 51/106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.8082G>A | p.Glu2694Glu | synonymous_variant | 51/105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000594335.5 | n.1533G>A | non_coding_transcript_exon_variant | 12/49 | 1 | ENSP00000470927.2 | ||||
RYR1 | ENST00000599547.6 | n.8082G>A | non_coding_transcript_exon_variant | 51/80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251464Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135920
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461862Hom.: 0 Cov.: 43 AF XY: 0.0000165 AC XY: 12AN XY: 727236
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Malignant hyperthermia of anesthesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Multiminicore myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Neuromuscular disease, congenital, with uniform type 1 fiber Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Central core myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Malignant hyperthermia, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | - - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at