NM_001035.3:c.14757-7_14757-6delTCinsAT
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001035.3(RYR2):c.14757-7_14757-6delTCinsAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001035.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.14757-7_14757-6delTCinsAT | splice_region_variant, intron_variant | Intron 103 of 104 | 1 | NM_001035.3 | ENSP00000355533.2 | |||
RYR2 | ENST00000609119.2 | n.*5849-7_*5849-6delTCinsAT | splice_region_variant, intron_variant | Intron 102 of 103 | 5 | ENSP00000499659.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
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not specified Uncertain:1Benign:1
The 14757-7_14757-6delinsAT variant in RYR2 has been reported in 3 individuals w ith CPVT or sudden death (Tan 2005, Hofman 2010, van der Werf 2012), though 1 in dividual carried other variants of unknown significance and in another family, a t least 4 relatives carried the variant and were unaffected (ages not specified) . This variant is located in the 3' splice region. Computational tools do not su ggest an impact to splicing, though this information is not predictive enough to determine pathogenicity. While the presence of this variant in multiple affecte d individuals suggests that it may play a role in disease, the presence in multi ple unaffected relatives brings into question its ability to cause disease in is olation. In summary, additional information is needed to fully assess the clinic al significance of this variant. -
Variant summary: RYR2 c.14757-7_14757-6delinsAT alters two nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant has also been reported in the literature as c.14757-6C>T; c.14757-7T>A . Although the combined variant c.14757-7_14757-6delinsA is not reported in population databases, it appears that most reads in gnomAD with c.14757-6C>T also carry c.14757-7T>A . Thus, it can be estimated that the combined allele c.14757-7_14757-6delinsA was found at a frequency of approximately 0.00021 in 275638 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 16.8- fold the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.14757-7_14757-6delinsAT has been reported in the literature in at least 3 probands with catecholaminergic polymorphic ventricular tachycardia (CPVT) and/or sudden death, without strong evidence for causality (examples- Tan_2005, Hofman_2010, vanderWerf_2012). The variant was also found in unaffected family members (example-Hofman_2010), and segregation with disease was not clear. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiomyopathy Uncertain:1Benign: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