rs753733164

chr1-237784887-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4 BP6 BS1 BS2

The NM_001035.3(RYR2):c.13175A>G(p.Lys4392Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000093 in 1,613,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (3 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 3.71

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.33532923).
• BP6: Variant 1-237784887-A-G is Benign according to our data. Variant chr1-237784887-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575869.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=5, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000592 (9/152112) while in subpopulation EAS AF= 0.00174 (9/5166). AF 95% confidence interval is 0.000909. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.13175A>G	p.Lys4392Arg	missense_variant	90/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.13175A>G	p.Lys4392Arg	missense_variant	90/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.13196A>G	p.Lys4399Arg	missense_variant	91/106
RYR2	ENST00000659194.3	c.13163A>G	p.Lys4388Arg	missense_variant	90/105
RYR2	ENST00000609119.2	c.*4267A>G		3_prime_UTR_variant, NMD_transcript_variant	89/104	5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000162 AC: 4 AN: 246870 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133966

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000225

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461068 Hom.: 3 Cov.: 33 AF XY: 0.0000798 AC XY: 58 AN XY: 726742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00348

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.00000827 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 02, 2023

This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated Japanese affected with catecholaminergic polymorphic ventricular tachycardia, as well as in a few asymptomatic carriers in their families (PMID: 23595086, 25092222). This variant has also been reported in an individual affected with idiopathic bradyarrhythmia (PMID: 36070930). This variant has been identified in 4/246870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 09, 2023

This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated Japanese affected with catecholaminergic polymorphic ventricular tachycardia, as well as in a few asymptomatic carriers in their families (PMID: 23595086, 25092222). This variant has also been reported in an individual affected with idiopathic bradyarrhythmia (PMID: 36070930). This variant has been identified in 4/246870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2021

The p.K4392R variant (also known as c.13175A>G), located in coding exon 90 of the RYR2 gene, results from an A to G substitution at nucleotide position 13175. The lysine at codon 4392 is replaced by arginine, an amino acid with highly similar properties. This variant has been detected in the heterozygous state in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) and in asymptomatic relatives (Arakawa J et al. Heart Vessels, 2015 Nov;30:835-40; Kawata H et al. Circ J, 2016 Aug;80:1907-15; Kawamura M et al. Circ J, 2013 Apr;77:1705-13). This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 16, 2023

Variant summary: RYR2 c.13175A>G (p.Lys4392Arg) results in a conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 324312 control chromosomes, including 2 homozygotes (gnomAD and jMorp databases (Tadaka_2021)). The observed variant frequency is approximately 41.62 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.13175A>G has been reported in the literature in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia, however, the variant was also identified in unaffected individuals and found to not segregate with disease among related individuals (e.g., Kawamura_2013, Arakawa_2015). Additionally, in one proband with catecholaminergic polymorphic ventricular tachycardia, a co-occurrence with another pathogenic variant was reported (RYR2 c.12006G>A, p.M4002I; Kawamura_2013), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant showed no damaging effect on the cytosolic calcium-dependent activity of RYR2 (e.g., Kurebayashi_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25092222, 23595086, 35446340, 33179747). Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: 3 submitters classified the variant as uncertain significance, and one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	14
Dann	Benign	0.26
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.85	T;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.79	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.40	N;.
REVEL	Pathogenic	0.69
Sift	Benign	0.57	T;.
Polyphen		0.0010	B;.
Vest4		0.71
MutPred		0.41		Loss of ubiquitination at K4392 (P = 0.0087);.;
MVP		0.73
MPC		0.68
ClinPred		0.052	T
GERP RS		3.5
Varity_R		0.050
gMVP		0.24

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

Other links and lift over

dbSNP: rs753733164; hg19: chr1-237948187;