rs397516531
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2
The NM_001035.3(RYR2):c.4329G>A(p.Val1443=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,844 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 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
RYR2
NM_001035.3 synonymous
NM_001035.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.132
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 -8 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
?
Variant 1-237593529-G-A is Benign according to our data. Variant chr1-237593529-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43783.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BP7
?
Synonymous conserved (PhyloP=0.132 with no splicing effect.
BS2
?
High AC in GnomAdExome4 at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.4329G>A | p.Val1443= | synonymous_variant | 33/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.4329G>A | p.Val1443= | synonymous_variant | 33/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.4329G>A | p.Val1443= | synonymous_variant | 33/106 | ||||
RYR2 | ENST00000659194.3 | c.4329G>A | p.Val1443= | synonymous_variant | 33/105 | ||||
RYR2 | ENST00000609119.2 | c.4329G>A | p.Val1443= | synonymous_variant, NMD_transcript_variant | 33/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152128Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 248948Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135044
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461598Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727084
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74442
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This variant is located in the RYR2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 3/280334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 09, 2011 | Val1443Val in exon 33 of RYR2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located nea r a splice junction. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | - - |
Computational scores
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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