rs780643623

Positions:

• chr1-237660919-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001035.3(RYR2):​c.8408G>A​(p.Arg2803Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000213 in 1,313,652 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2803W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.63

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 -5 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=0.25718957).
• BS2: High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.8408G>A	p.Arg2803Gln	missense_variant	56/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.8408G>A	p.Arg2803Gln	missense_variant	56/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.8408G>A		non_coding_transcript_exon_variant	56/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.8408G>A	p.Arg2803Gln	missense_variant	56/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.8408G>A	p.Arg2803Gln	missense_variant	56/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000156 AC: 2 AN: 128032 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000579

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 28 AN: 1313652 Hom.: 0 Cov.: 30 AF XY: 0.0000264 AC XY: 17 AN XY: 643738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000193

Gnomad4 OTH exome AF: 0.0000371

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000413 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000335 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2023	This missense variant replaces arginine with glutamine at codon 2803 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 2/128032 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 07, 2017	- -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces arginine with glutamine at codon 2803 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/128032 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2017

Although the R2803Q variant of uncertain significance in the RYR2 gene has not been published as pathogenic in association with arrhythmia or been reported as benign to our knowledge, it has been identified independently of additional cardiogenetic variants in one other individual referred for arrhythmia genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The R2803Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2803Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, the R2803Q variant is 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). Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	0.049
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.0	L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.80	N;.
REVEL	Uncertain	0.40
Sift	Benign	0.43	T;.
Polyphen		0.066	B;.
Vest4		0.22
MVP		0.77
MPC		0.42
ClinPred		0.32	T
GERP RS		5.5
Varity_R		0.12
gMVP		0.21

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: rs780643623; hg19: chr1-237824219; COSMIC: COSV63698303;