rs369774984
Variant summary
Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001035.3(RYR2):c.7094A>G(p.Asn2365Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2365D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
Publications
- arrhythmogenic right ventricular dysplasia 2Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
- catecholaminergic polymorphic ventricular tachycardiaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
- catecholaminergic polymorphic ventricular tachycardia 1Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- hypertrophic cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Benign. The variant received -12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.7094A>G | p.Asn2365Ser | missense_variant | Exon 46 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000661330.2 | c.7094A>G | p.Asn2365Ser | missense_variant | Exon 46 of 106 | ENSP00000499393.2 | ||||
RYR2 | ENST00000609119.2 | n.7094A>G | non_coding_transcript_exon_variant | Exon 46 of 104 | 5 | ENSP00000499659.2 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152224Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000121 AC: 3AN: 248666 AF XY: 0.00000741 show subpopulations
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461150Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726796 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152342Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74496 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
This missense variant replaces asparagine with serine at codon 2365 of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/280064 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Cardiovascular phenotype Uncertain:1
The p.N2365S variant (also known as c.7094A>G), located in coding exon 46 of the RYR2 gene, results from an A to G substitution at nucleotide position 7094. The asparagine at codon 2365 is replaced by serine, an amino acid with highly similar properties. This alteration was reported in a whole exome sequencing cohort; however, clinical data was limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Cardiomyopathy Benign:1
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Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at