1-237793861-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000366574.7(RYR2):​c.13783-6A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,589,870 control chromosomes in the GnomAD database, including 391,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 35626 hom., cov: 32)
Exomes 𝑓: 0.70 ( 355847 hom. )

Consequence

RYR2
ENST00000366574.7 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.000008101
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -1.42
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 1-237793861-A-G is Benign according to our data. Variant chr1-237793861-A-G is described in ClinVar as [Benign]. Clinvar id is 43731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237793861-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR2NM_001035.3 linkuse as main transcriptc.13783-6A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000366574.7 NP_001026.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkuse as main transcriptc.13783-6A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_001035.3 ENSP00000355533 P1Q92736-1

Frequencies

GnomAD3 genomes
AF:
0.679
AC:
103170
AN:
151848
Hom.:
35604
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.590
Gnomad AMI
AF:
0.832
Gnomad AMR
AF:
0.750
Gnomad ASJ
AF:
0.642
Gnomad EAS
AF:
0.954
Gnomad SAS
AF:
0.862
Gnomad FIN
AF:
0.696
Gnomad MID
AF:
0.665
Gnomad NFE
AF:
0.682
Gnomad OTH
AF:
0.655
GnomAD3 exomes
AF:
0.738
AC:
180422
AN:
244512
Hom.:
67893
AF XY:
0.739
AC XY:
97904
AN XY:
132442
show subpopulations
Gnomad AFR exome
AF:
0.586
Gnomad AMR exome
AF:
0.825
Gnomad ASJ exome
AF:
0.655
Gnomad EAS exome
AF:
0.947
Gnomad SAS exome
AF:
0.862
Gnomad FIN exome
AF:
0.708
Gnomad NFE exome
AF:
0.680
Gnomad OTH exome
AF:
0.704
GnomAD4 exome
AF:
0.699
AC:
1005342
AN:
1437904
Hom.:
355847
Cov.:
28
AF XY:
0.704
AC XY:
504058
AN XY:
716162
show subpopulations
Gnomad4 AFR exome
AF:
0.583
Gnomad4 AMR exome
AF:
0.818
Gnomad4 ASJ exome
AF:
0.655
Gnomad4 EAS exome
AF:
0.950
Gnomad4 SAS exome
AF:
0.858
Gnomad4 FIN exome
AF:
0.703
Gnomad4 NFE exome
AF:
0.677
Gnomad4 OTH exome
AF:
0.697
GnomAD4 genome
AF:
0.679
AC:
103237
AN:
151966
Hom.:
35626
Cov.:
32
AF XY:
0.686
AC XY:
50928
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.590
Gnomad4 AMR
AF:
0.750
Gnomad4 ASJ
AF:
0.642
Gnomad4 EAS
AF:
0.954
Gnomad4 SAS
AF:
0.862
Gnomad4 FIN
AF:
0.696
Gnomad4 NFE
AF:
0.682
Gnomad4 OTH
AF:
0.658
Alfa
AF:
0.674
Hom.:
44424
Bravo
AF:
0.678
Asia WGS
AF:
0.877
AC:
3046
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingGeneDxJul 07, 2011This 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. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 16, 2011- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 15, 2014- -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Arrhythmogenic right ventricular dysplasia 2 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 09, 2018- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Cardiac arrhythmia Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
2.0
DANN
Benign
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0000081
dbscSNV1_RF
Benign
0.0
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs790901; hg19: chr1-237957161; API