rs202225176
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_000540.3(RYR1):c.5287C>T(p.Pro1763Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,714 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 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
RYR1
NM_000540.3 missense
NM_000540.3 missense
Scores
3
8
7
Clinical Significance
Conservation
PhyloP100: 7.83
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 -2 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.
BP4
Computational evidence support a benign effect (MetaRNN=0.16495398).
BP6
Variant 19-38485942-C-T is Benign according to our data. Variant chr19-38485942-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478237.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.5287C>T | p.Pro1763Ser | missense_variant | 34/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.5287C>T | p.Pro1763Ser | missense_variant | 34/106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.5287C>T | p.Pro1763Ser | missense_variant | 34/105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000599547.6 | n.5287C>T | non_coding_transcript_exon_variant | 34/80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000530 AC: 13AN: 245134Hom.: 0 AF XY: 0.0000301 AC XY: 4AN XY: 132946
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461398Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12AN XY: 726984
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GnomAD4 genome AF: 0.0000525 AC: 8AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74460
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 20, 2019 | - - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 23, 2021 | - - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Benign
T;T
Polyphen
D;B
Vest4
MVP
MPC
0.62
ClinPred
T
GERP RS
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gMVP
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