rs748194372
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BS1_SupportingBS2
The NM_001035.3(RYR2):c.9407G>A(p.Ser3136Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,456,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S3136C) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.9407G>A | p.Ser3136Asn | missense_variant | 66/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.9407G>A | p.Ser3136Asn | missense_variant | 66/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.9407G>A | p.Ser3136Asn | missense_variant | 66/106 | ||||
RYR2 | ENST00000659194.3 | c.9407G>A | p.Ser3136Asn | missense_variant | 66/105 | ||||
RYR2 | ENST00000609119.2 | c.*442G>A | 3_prime_UTR_variant, NMD_transcript_variant | 64/104 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248596Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134832
GnomAD4 exome AF: 0.00000755 AC: 11AN: 1456592Hom.: 0 Cov.: 27 AF XY: 0.0000110 AC XY: 8AN XY: 724988
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 21, 2019 | This missense variant replaces serine with asparagine at codon 3136 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 2/248596 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 | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Jul 27, 2019 | Updated local variant frequency is incompatible with the prior classification of this variant as likely pathogenic. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 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: 190998). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs748194372, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 3136 of the RYR2 protein (p.Ser3136Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at