chr1-237492989-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001035.3(RYR2):​c.1863C>T​(p.His621His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,606,154 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 5 hom., cov: 32)
Exomes 𝑓: 0.0070 ( 44 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.449

Publications

4 publications found
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]
RYR2 Gene-Disease associations (from GenCC):
  • arrhythmogenic right ventricular dysplasia 2
    Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
  • catecholaminergic polymorphic ventricular tachycardia
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
  • catecholaminergic polymorphic ventricular tachycardia 1
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.44).
BP6
Variant 1-237492989-C-T is Benign according to our data. Variant chr1-237492989-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.449 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00461 (701/152140) while in subpopulation NFE AF = 0.00765 (520/68008). AF 95% confidence interval is 0.0071. There are 5 homozygotes in GnomAd4. There are 325 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 701 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.1863C>T p.His621His synonymous_variant Exon 19 of 105 ENST00000366574.7 NP_001026.2 Q92736-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkc.1863C>T p.His621His synonymous_variant Exon 19 of 105 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000661330.2 linkc.1863C>T p.His621His synonymous_variant Exon 19 of 106 ENSP00000499393.2 A0A590UJF6
RYR2ENST00000609119.2 linkn.1863C>T non_coding_transcript_exon_variant Exon 19 of 104 5 ENSP00000499659.2 A0A590UK06

Frequencies

GnomAD3 genomes
AF:
0.00461
AC:
701
AN:
152022
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00133
Gnomad AMI
AF:
0.00329
Gnomad AMR
AF:
0.00531
Gnomad ASJ
AF:
0.00519
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.000473
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00765
Gnomad OTH
AF:
0.00574
GnomAD2 exomes
AF:
0.00483
AC:
1150
AN:
238326
AF XY:
0.00476
show subpopulations
Gnomad AFR exome
AF:
0.000836
Gnomad AMR exome
AF:
0.00589
Gnomad ASJ exome
AF:
0.00376
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000707
Gnomad NFE exome
AF:
0.00739
Gnomad OTH exome
AF:
0.00801
GnomAD4 exome
AF:
0.00704
AC:
10242
AN:
1454014
Hom.:
44
Cov.:
33
AF XY:
0.00681
AC XY:
4919
AN XY:
722432
show subpopulations
African (AFR)
AF:
0.000988
AC:
33
AN:
33414
American (AMR)
AF:
0.00610
AC:
267
AN:
43780
Ashkenazi Jewish (ASJ)
AF:
0.00439
AC:
113
AN:
25738
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39648
South Asian (SAS)
AF:
0.00188
AC:
160
AN:
84902
European-Finnish (FIN)
AF:
0.00117
AC:
62
AN:
53110
Middle Eastern (MID)
AF:
0.0149
AC:
86
AN:
5766
European-Non Finnish (NFE)
AF:
0.00826
AC:
9152
AN:
1107540
Other (OTH)
AF:
0.00614
AC:
369
AN:
60116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
525
1049
1574
2098
2623
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
354
708
1062
1416
1770
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00461
AC:
701
AN:
152140
Hom.:
5
Cov.:
32
AF XY:
0.00437
AC XY:
325
AN XY:
74372
show subpopulations
African (AFR)
AF:
0.00133
AC:
55
AN:
41498
American (AMR)
AF:
0.00530
AC:
81
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00519
AC:
18
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5168
South Asian (SAS)
AF:
0.000830
AC:
4
AN:
4820
European-Finnish (FIN)
AF:
0.000473
AC:
5
AN:
10576
Middle Eastern (MID)
AF:
0.0102
AC:
3
AN:
294
European-Non Finnish (NFE)
AF:
0.00765
AC:
520
AN:
68008
Other (OTH)
AF:
0.00568
AC:
12
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
36
73
109
146
182
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00551
Hom.:
3
Bravo
AF:
0.00480
Asia WGS
AF:
0.00202
AC:
7
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Mar 13, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

His621His in exon 19 of RYR2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and has been identified in 0.8% (53/6742) from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17686573). -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Dec 23, 2014
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:5
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Nov 21, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

RYR2: BP4, BP7, BS2 -

Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Cardiomyopathy Benign:3
Dec 26, 2013
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 29, 2016
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 08, 2018
Color Diagnostics, LLC DBA Color Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Catecholaminergic polymorphic ventricular tachycardia Benign:1
Feb 05, 2024
All of Us Research Program, National Institutes of Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1
Jun 01, 2015
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.44
CADD
Benign
7.3
DANN
Benign
0.35
PhyloP100
0.45
Mutation Taster
=91/9
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs17686573; hg19: chr1-237656289; API