rs577451406
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001035.3(RYR2):c.2410C>T(p.Leu804Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,608,686 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 1 hom. )
Consequence
RYR2
NM_001035.3 missense
NM_001035.3 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 2.89
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 -19 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, RYR2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.037508428).
BP6
?
Variant 1-237503302-C-T is Benign according to our data. Variant chr1-237503302-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 532409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000526 (8/152222) while in subpopulation EAS AF= 0.00155 (8/5178). AF 95% confidence interval is 0.000768. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.2410C>T | p.Leu804Phe | missense_variant | 22/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.2410C>T | p.Leu804Phe | missense_variant | 22/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.2410C>T | p.Leu804Phe | missense_variant | 22/106 | ||||
RYR2 | ENST00000659194.3 | c.2410C>T | p.Leu804Phe | missense_variant | 22/105 | ||||
RYR2 | ENST00000609119.2 | c.2410C>T | p.Leu804Phe | missense_variant, NMD_transcript_variant | 22/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000113 AC: 27AN: 239496Hom.: 1 AF XY: 0.000116 AC XY: 15AN XY: 129832
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GnomAD4 exome AF: 0.0000206 AC: 30AN: 1456464Hom.: 1 Cov.: 31 AF XY: 0.0000166 AC XY: 12AN XY: 723948
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74430
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ClinVar
Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 18, 2018 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Benign
T;.
Polyphen
D;.
Vest4
MutPred
Gain of sheet (P = 0.0827);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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