rs397516534
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_001035.3(RYR2):c.463+6dup variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,609,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
RYR2
NM_001035.3 splice_donor_region, intron
NM_001035.3 splice_donor_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.291
Genes affected
RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
?
Variant 1-237374800-G-GC is Benign according to our data. Variant chr1-237374800-G-GC is described in ClinVar as [Likely_benign]. Clinvar id is 43789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000354 (54/152346) while in subpopulation AFR AF= 0.00127 (53/41584). AF 95% confidence interval is 0.001. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 54 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.463+6dup | splice_donor_region_variant, intron_variant | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.463+6dup | splice_donor_region_variant, intron_variant | 1 | NM_001035.3 | P1 | |||
RYR2 | ENST00000659194.3 | c.463+6dup | splice_donor_region_variant, intron_variant | ||||||
RYR2 | ENST00000660292.2 | c.463+6dup | splice_donor_region_variant, intron_variant | ||||||
RYR2 | ENST00000609119.2 | c.463+6dup | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000355 AC: 54AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000991 AC: 24AN: 242278Hom.: 0 AF XY: 0.0000686 AC XY: 9AN XY: 131108
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GnomAD4 exome AF: 0.0000220 AC: 32AN: 1457416Hom.: 0 Cov.: 30 AF XY: 0.0000166 AC XY: 12AN XY: 724504
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GnomAD4 genome ? AF: 0.000354 AC: 54AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74498
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 18, 2012 | 463+6_463+7insC in intron 7 of RYR2: This variant is not expected to have clinic al significance because it is not located within the splice consensus sequence. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 22, 2019 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at