rs193922624

Positions:

• chr1-237566603-G-A
• chr1-237566603-G-C
• chr1-237566603-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001035.3(RYR2):​c.3251G>A​(p.Arg1084Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1084M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 1.40

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07539654).
• BP6: Variant 1-237566603-G-A is Benign according to our data. Variant chr1-237566603-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36740.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr1-237566603-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.3251G>A	p.Arg1084Lys	missense_variant	28/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.3251G>A	p.Arg1084Lys	missense_variant	28/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.3251G>A		non_coding_transcript_exon_variant	28/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.3251G>A	p.Arg1084Lys	missense_variant	28/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.3251G>A	p.Arg1084Lys	missense_variant	28/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 249038 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000276 AC: 404 AN: 1461668 Hom.: 0 Cov.: 31 AF XY: 0.000252 AC XY: 183 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000325

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000149 AC: 18

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2019	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 21, 2014	Arg1084Lys in exon 28 of RYR2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, opossum, tasmanian devil, and wallaby have a lysine (Lys) at this position a s well as several birds and reptiles despite high nearby amino acid conservation . In addition, computational analyses (AlignGVGD, PolyPhen2, SIFT) do not sugges t a high likelihood of impact to the protein. Arg1084Lys in exon 28 of RYR2 (rs 193922624; allele frequency = n/a) -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 14, 2011	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p. Arg1084Lys (c.3251G>A) in the RYR2 gene. This variant is novel. It has not been reported in association with disease or as a benign polymorphism. In silico analysis with PolyPhen-2 predicts the variant to be benign. This is a chemically conservative change with a polar positive amino acid replacing another polar positive amino acid. The variant is not conserved across evolution and is in fact a lysine in zebra finch and green puffer. The variant is not listed in dbSNP or 1000 genomes (as of August 2011). Medeiros-Domingo et al (2009) reported that 3% of individuals from the general population carry a rare or novel variant in RYR2. Variants in RYR2 have not been linked to HCM. Other variants in RYR2 have been associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). Variants in this gene have also been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), though this association is debated. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Jul 16, 2014

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 18, 2019

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2020

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. -

Cardiac arrhythmia Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

Oct 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	-0.025	N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.51	N;.
REVEL	Uncertain	0.29
Sift	Benign	0.98	T;.
Polyphen		0.0	B;.
Vest4		0.33
MVP		0.57
MPC		0.36
ClinPred		0.031	T
GERP RS		4.2
Varity_R		0.087
gMVP		0.51

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: rs193922624; hg19: chr1-237729903; COSMIC: COSV63725288;