rs1555781547
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_000540.3(RYR1):c.6295_6351dupTCCCACATGGTGGTGCGCTGGGCCCAAGAGGACTTCGTGCAGAGCCCCGAGCTGGTG(p.Ser2099_Val2117dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
RYR1
NM_000540.3 conservative_inframe_insertion
NM_000540.3 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.19
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]
Genome browser will be placed here
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;
PM4
Nonframeshift variant in NON repetitive region in NM_000540.3.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.6295_6351dupTCCCACATGGTGGTGCGCTGGGCCCAAGAGGACTTCGTGCAGAGCCCCGAGCTGGTG | p.Ser2099_Val2117dup | conservative_inframe_insertion | 39/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.6295_6351dupTCCCACATGGTGGTGCGCTGGGCCCAAGAGGACTTCGTGCAGAGCCCCGAGCTGGTG | p.Ser2099_Val2117dup | conservative_inframe_insertion | 39/106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.6295_6351dupTCCCACATGGTGGTGCGCTGGGCCCAAGAGGACTTCGTGCAGAGCCCCGAGCTGGTG | p.Ser2099_Val2117dup | conservative_inframe_insertion | 39/105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000599547.6 | n.6295_6351dupTCCCACATGGTGGTGCGCTGGGCCCAAGAGGACTTCGTGCAGAGCCCCGAGCTGGTG | non_coding_transcript_exon_variant | 39/80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459160Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725900
GnomAD4 exome
AF:
AC:
4
AN:
1459160
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
725900
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 09, 2017 | This sequence change inserts 57 nucleotides in exon 39 of the RYR1 mRNA (c.6295_6351dup). This leads to the duplication of 19 amino acid residues in the RYR1 protein (p.Ser2099_Val2117dup) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals a with a RYR1-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the inserted amino acids is currently unknown. In summary, this is a novel in-frame duplication with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at