rs878854157
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2
The ENST00000366574.7(RYR2):c.4596+3_4596+9del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,607,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
RYR2
ENST00000366574.7 splice_donor, splice_donor_5th_base, coding_sequence, intron
ENST00000366574.7 splice_donor, splice_donor_5th_base, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.010668277 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.9, offset of 0 (no position change), new splice context is: cagGTcagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
BS2
High AC in GnomAdExome4 at 28 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.4596+3_4596+9del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 34/105 | ENST00000366574.7 | NP_001026.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.4596+3_4596+9del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 34/105 | 1 | NM_001035.3 | ENSP00000355533 | P1 | ||
RYR2 | ENST00000659194.3 | c.4596+3_4596+9del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 34/105 | ENSP00000499653 | |||||
RYR2 | ENST00000660292.2 | c.4596+3_4596+9del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 34/106 | ENSP00000499787 | |||||
RYR2 | ENST00000609119.2 | c.4596+3_4596+9del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant, NMD_transcript_variant | 34/104 | 5 | ENSP00000499659 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000372 AC: 9AN: 241818Hom.: 0 AF XY: 0.0000609 AC XY: 8AN XY: 131386
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1455548Hom.: 0 AF XY: 0.0000318 AC XY: 23AN XY: 723834
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 30, 2018 | This sequence change falls in intron 34 of the RYR2 gene. It does not directly change the encoded amino acid sequence of the RYR2 protein, but it affects a nucleotide within the consensus splice site of the intron. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 238234). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at