rs774892189
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_000540.3(RYR1):c.800+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,670 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
RYR1
NM_000540.3 splice_donor_region, intron
NM_000540.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00007773
2
Clinical Significance
Conservation
PhyloP100: -0.786
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=-0.91).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.800+4G>A | splice_donor_region_variant, intron_variant | ENST00000359596.8 | NP_000531.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.800+4G>A | splice_donor_region_variant, intron_variant | 5 | NM_000540.3 | ENSP00000352608 | A2 | |||
RYR1 | ENST00000355481.8 | c.800+4G>A | splice_donor_region_variant, intron_variant | 1 | ENSP00000347667 | P4 | ||||
RYR1 | ENST00000599547.6 | c.800+4G>A | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 2 | ENSP00000471601 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460670Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726618
GnomAD4 exome
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6
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1460670
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31
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4
AN XY:
726618
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | This sequence change falls in intron 9 of the RYR1 gene. It does not directly change the encoded amino acid sequence of the RYR1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs774892189, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 590602). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 30, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at