rs193922623

chr1-237500774-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_001035.3(RYR2):c.2267G>A(p.Ser756Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:7
• Conservation: PhyloP100: 9.99

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP6: Variant 1-237500774-G-A is Benign according to our data. Variant chr1-237500774-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36739.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}.
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.2267G>A	p.Ser756Asn	missense_variant	21/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.2267G>A	p.Ser756Asn	missense_variant	21/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.2267G>A	p.Ser756Asn	missense_variant	21/106
RYR2	ENST00000659194.3	c.2267G>A	p.Ser756Asn	missense_variant	21/105
RYR2	ENST00000609119.2	c.2267G>A	p.Ser756Asn	missense_variant, NMD_transcript_variant	21/104	5

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000217 AC: 54 AN: 249214 Hom.: 0 AF XY: 0.000222 AC XY: 30 AN XY: 135196

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1461680 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 80 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000444 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000199 AC: 24

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2023	Reported in association with HCM, DCM, and sudden unexplained death (Lopes et al., 2015; Subbotina et al., 2019; Burstein et al., 2021); Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30878466, 19926015, 28404607, 32746448, 25351510) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 01, 2017	p.Ser756Asn (c.2267G>A) in the RYR2 gene (NM_001035.2; chr1-237664074-G-A) SCICD Classification: variant of uncertain significance, likely benign based on limited data to associate this gene with disease and relatively high frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: RYR2 has not been associated with HCM Region-level evidence: Per the lab report, this variant is not in one of the regions of RYR2 that is enriched for pathogenic variation. Population data: Highest MAF in Ashkenazi Jewish population: 0.4630%. The variant was reported online in 56 of 138571 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2017	Variant summary: The RYR2 c.2267G>A (p.Ser756Asn) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict damaging outcome for this variant. This variant was found in 24/120700 control chromosomes from ExAC at a frequency of 0.0001988, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. In addition, this variant has been detected at an allele frequency of ~0.5% (47/10152 chromosomes) in Ashkenazi subpopulation in gnomAD database, further supporting benign outcome. However, five clinical diagnostic laboratories (via ClinVar) have classified this variant as uncertain significance. LMM (via ClinVar) has reported this variant in two Caucasian adults with DCM and one Ashkenazi Jewish adult with HCM and has classified the variant as a VUS, although they do not report if this variant was found with other pathogenic variants in other genes, do not provide any familial co-segregation analysis and have not used ExAC data at that time. Due to the possibility of low penetrance pathogenic variants in the control population and unknown status of cardiological information in control populations, possibility of digenic inheritance in arrythmias and due to lack of functional and clinical data for this variant, the variant has been classified as a VUS-possibly benign until additional evidence becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2018	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 28, 2017	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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. -

Ventricular fibrillation, paroxysmal familial, type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Mar 20, 2014

- -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 22, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2019

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Uncertain	0.46
Sift	Benign	0.066	T;T
Polyphen		1.0	D;.
Vest4		0.76
MVP		0.82
MPC		1.1
ClinPred		0.41	T
GERP RS		5.8
Varity_R		0.58
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: 12

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922623; hg19: chr1-237664074;