rs369982130
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001035.3(RYR2):c.4096A>G(p.Thr1366Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. T1366N) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.4096A>G | p.Thr1366Ala | missense_variant | 31/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.4096A>G | p.Thr1366Ala | missense_variant | 31/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.4096A>G | p.Thr1366Ala | missense_variant | 31/106 | ||||
RYR2 | ENST00000659194.3 | c.4096A>G | p.Thr1366Ala | missense_variant | 31/105 | ||||
RYR2 | ENST00000609119.2 | c.4096A>G | p.Thr1366Ala | missense_variant, NMD_transcript_variant | 31/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152162Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000322 AC: 8AN: 248078Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134658
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461662Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727116
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152162Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74336
ClinVar
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 | Jan 03, 2024 | This missense variant replaces threonine with alanine at codon 1366 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/279484 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 01, 2023 | This missense variant replaces threonine with alanine at codon 1366 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/279484 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19926015) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2022 | The c.4096A>G (p.T1366A) alteration is located in exon 31 (coding exon 31) of the RYR2 gene. This alteration results from a A to G substitution at nucleotide position 4096, causing the threonine (T) at amino acid position 1366 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at