rs1008224442
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_001035.3(RYR2):āc.13449A>Gā(p.Lys4483=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,062 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 Likely benign (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000082 ( 0 hom. )
Consequence
RYR2
NM_001035.3 synonymous
NM_001035.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.55
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 Benign. Variant got -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
Variant 1-237788108-A-G is Benign according to our data. Variant chr1-237788108-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 463566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=1.55 with no splicing effect.
BS2
?
High AC in GnomAdExome4 at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.13449A>G | p.Lys4483= | synonymous_variant | 92/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.13449A>G | p.Lys4483= | synonymous_variant | 92/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.13470A>G | p.Lys4490= | synonymous_variant | 93/106 | ||||
RYR2 | ENST00000659194.3 | c.13431A>G | p.Lys4477= | synonymous_variant | 92/105 | ||||
RYR2 | ENST00000609119.2 | c.*4541A>G | 3_prime_UTR_variant, NMD_transcript_variant | 91/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000811 AC: 2AN: 246624Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133686
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GnomAD4 exome AF: 0.00000822 AC: 12AN: 1459816Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5AN XY: 726014
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74376
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Jan 14, 2022 | This synonymous variant is a silent variation that is not predicted to change the amino acid sequence of the protein and has occurred in gnomAD with a total MAF of 0.0008% and with the highest MAF of 0.0018% in the European population. This variant has been reported in ClinVar (463566) NM_001035.3(RYR2):c.13449A>G (p.Lys4483=). This position is not conserved. In silico splicing algorithms predicted no impact on splicing (not found in scSNV and is 28 bases away from the canonical splice-site in transcript, NM_001035.2). The variant has not occurred in the literature in the association with the disease. Considering the splice distance and that it is a silent change that does not have an apparent effect on RNA splicing machinery, the variant has been classified as Likely Benign. - |
Catecholaminergic polymorphic ventricular tachycardia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 30, 2023 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 30, 2018 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2022 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
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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