chr19-38490249-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000540.3(RYR1):c.5988C>T(p.Arg1996=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,772 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 Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
RYR1
NM_000540.3 synonymous
NM_000540.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.66
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RYR1 | NM_000540.3 | c.5988C>T | p.Arg1996= | synonymous_variant | 36/106 | ENST00000359596.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.5988C>T | p.Arg1996= | synonymous_variant | 36/106 | 5 | NM_000540.3 | A2 | |
| RYR1 | ENST00000355481.8 | c.5988C>T | p.Arg1996= | synonymous_variant | 36/105 | 1 | P4 | ||
| RYR1 | ENST00000599547.6 | c.5988C>T | p.Arg1996= | synonymous_variant, NMD_transcript_variant | 36/80 | 2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461772Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727184
GnomAD4 exome
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1461772
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32
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727184
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | RYR1 NM_000540.2 exon 36 p.Arg1996= (c.5988C>T): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar, but without additional information (Variation ID:133154). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, computational tools designed to predict splicing suggest that this variant may generate an alternate 5' splice site at this location. However, further studies are needed to understand its impact. Of note, this variant is a silent variant and does not change the amino acid. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. - |
not provided Other:1
| not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
DS_DL_spliceai
Position offset: 27
Find out detailed SpliceAI scores and Pangolin per-transcript scores at