rs767728159
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001035.3(RYR2):c.5416G>A(p.Ala1806Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1806V) 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.5416G>A | p.Ala1806Thr | missense_variant | 37/105 | ENST00000366574.7 | NP_001026.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.5416G>A | p.Ala1806Thr | missense_variant | 37/105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000609119.2 | n.5416G>A | non_coding_transcript_exon_variant | 37/104 | 5 | ENSP00000499659.2 | ||||
RYR2 | ENST00000660292.2 | c.5416G>A | p.Ala1806Thr | missense_variant | 37/106 | ENSP00000499787.2 | ||||
RYR2 | ENST00000659194.3 | c.5416G>A | p.Ala1806Thr | missense_variant | 37/105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248856Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134982
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727138
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 13, 2015 | The p.Ala1806Thr variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/66638 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Comput ational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rul e out pathogenicity. In summary, the clinical significance of the p.Ala1806Thr v ariant is uncertain. - |
Conduction disorder of the heart Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 18, 2017 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 15, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1806 of the RYR2 protein (p.Ala1806Thr). This variant is present in population databases (rs767728159, gnomAD 0.002%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 229220). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at