rs151313865
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000540.3(RYR1):c.6498C>T(p.Leu2166Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,614,152 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0064 ( 6 hom., cov: 31)
Exomes 𝑓: 0.00066 ( 5 hom. )
Consequence
RYR1
NM_000540.3 synonymous
NM_000540.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.508
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 Benign. Variant got -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
Variant 19-38494575-C-T is Benign according to our data. Variant chr19-38494575-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38494575-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.508 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00644 (981/152348) while in subpopulation AFR AF= 0.0223 (929/41586). AF 95% confidence interval is 0.0211. There are 6 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RYR1 | NM_000540.3 | c.6498C>T | p.Leu2166Leu | synonymous_variant | 39/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.6498C>T | p.Leu2166Leu | synonymous_variant | 39/106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.6498C>T | p.Leu2166Leu | synonymous_variant | 39/105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000599547.6 | n.6498C>T | non_coding_transcript_exon_variant | 39/80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes 0.00640 AC: 975AN: 152230Hom.: 6 Cov.: 31
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GnomAD3 exomes AF: 0.00176 AC: 441AN: 250386Hom.: 2 AF XY: 0.00125 AC XY: 169AN XY: 135524
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GnomAD4 exome AF: 0.000662 AC: 968AN: 1461804Hom.: 5 Cov.: 32 AF XY: 0.000579 AC XY: 421AN XY: 727198
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GnomAD4 genome 0.00644 AC: 981AN: 152348Hom.: 6 Cov.: 31 AF XY: 0.00633 AC XY: 472AN XY: 74508
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 10, 2014 | - - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 13, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Malignant hyperthermia, susceptibility to, 1 Benign:3
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 20, 2022 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
| Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Congenital multicore myopathy with external ophthalmoplegia Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
RYR1-related disorder Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Central core myopathy Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 08, 2021 | - - |
Computational scores
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Name
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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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at