chr1-237648589-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001035.3(RYR2):​c.7488C>T​(p.Leu2496=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,610,118 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 33)
Exomes 𝑓: 0.0045 ( 21 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.294
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.31).
BP6
Variant 1-237648589-C-T is Benign according to our data. Variant chr1-237648589-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237648589-C-T is described in Lovd as [Benign]. Variant chr1-237648589-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.294 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0038 (579/152254) while in subpopulation NFE AF= 0.00488 (332/68018). AF 95% confidence interval is 0.00445. There are 3 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 579 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR2NM_001035.3 linkuse as main transcriptc.7488C>T p.Leu2496= synonymous_variant 49/105 ENST00000366574.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR2ENST00000366574.7 linkuse as main transcriptc.7488C>T p.Leu2496= synonymous_variant 49/1051 NM_001035.3 P1Q92736-1
RYR2ENST00000660292.2 linkuse as main transcriptc.7488C>T p.Leu2496= synonymous_variant 49/106
RYR2ENST00000659194.3 linkuse as main transcriptc.7488C>T p.Leu2496= synonymous_variant 49/105
RYR2ENST00000609119.2 linkuse as main transcriptc.7488C>T p.Leu2496= synonymous_variant, NMD_transcript_variant 49/1045

Frequencies

GnomAD3 genomes
AF:
0.00381
AC:
579
AN:
152136
Hom.:
3
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00106
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00223
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00166
Gnomad FIN
AF:
0.0141
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00488
Gnomad OTH
AF:
0.00382
GnomAD3 exomes
AF:
0.00377
AC:
914
AN:
242464
Hom.:
3
AF XY:
0.00376
AC XY:
494
AN XY:
131298
show subpopulations
Gnomad AFR exome
AF:
0.000813
Gnomad AMR exome
AF:
0.00100
Gnomad ASJ exome
AF:
0.000712
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00150
Gnomad FIN exome
AF:
0.0143
Gnomad NFE exome
AF:
0.00454
Gnomad OTH exome
AF:
0.00253
GnomAD4 exome
AF:
0.00453
AC:
6601
AN:
1457864
Hom.:
21
Cov.:
30
AF XY:
0.00452
AC XY:
3278
AN XY:
724714
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.00115
Gnomad4 ASJ exome
AF:
0.000616
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00178
Gnomad4 FIN exome
AF:
0.0144
Gnomad4 NFE exome
AF:
0.00488
Gnomad4 OTH exome
AF:
0.00279
GnomAD4 genome
AF:
0.00380
AC:
579
AN:
152254
Hom.:
3
Cov.:
33
AF XY:
0.00446
AC XY:
332
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.00106
Gnomad4 AMR
AF:
0.00222
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.0141
Gnomad4 NFE
AF:
0.00488
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.00334
Hom.:
0
Bravo
AF:
0.00249
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 24, 2012Leu2496Leu in Exon 49 of RYR2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.6% (39/6624) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs143906555). -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 27, 2013- -
not provided Benign:4
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024RYR2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Cardiomyopathy Benign:2
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioSep 02, 2016- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 08, 2018- -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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 testingInvitaeFeb 01, 2024- -
Catecholaminergic polymorphic ventricular tachycardia Benign:1
Benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
Arrhythmogenic right ventricular dysplasia 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Cardiac arrhythmia Benign:1
Benign, no assertion criteria providedclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 07, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.31
CADD
Benign
6.5
DANN
Benign
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs143906555; hg19: chr1-237811889; API