rs878854154
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001035.3(RYR2):āc.2251A>Gā(p.Thr751Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,828 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T751I) 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.2251A>G | p.Thr751Ala | missense_variant | 21/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.2251A>G | p.Thr751Ala | missense_variant | 21/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.2251A>G | p.Thr751Ala | missense_variant | 21/106 | ||||
RYR2 | ENST00000659194.3 | c.2251A>G | p.Thr751Ala | missense_variant | 21/105 | ||||
RYR2 | ENST00000609119.2 | c.2251A>G | p.Thr751Ala | missense_variant, NMD_transcript_variant | 21/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461634Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727092
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
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 | Feb 05, 2024 | This missense variant replaces threonine with alanine at codon 751 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on 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 1/31398 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 20, 2023 | This missense variant replaces threonine with alanine at codon 751 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). 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 1/31398 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 | Jan 16, 2017 | A variant of uncertain significance has been identified in the RYR2 gene. The T751A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T751A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, Alanine is the wild-type amino acid at this position in at least three species. In addition, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the T751A variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 238227). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 751 of the RYR2 protein (p.Thr751Ala). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at