1-237660868-G-T

Position:

• chr1-237660868-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2 PP3_Strong BS2

The NM_001035.3(RYR2):​c.8357G>T​(p.Gly2786Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000646 in 1,392,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2786A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.54

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 Uncertain_significance. Variant got 1 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.8357G>T	p.Gly2786Val	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.8357G>T	p.Gly2786Val	missense_variant	56/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.8357G>T		non_coding_transcript_exon_variant	56/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.8357G>T	p.Gly2786Val	missense_variant	56/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.8357G>T	p.Gly2786Val	missense_variant	56/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000646 AC: 9 AN: 1392736 Hom.: 0 Cov.: 30 AF XY: 0.00000291 AC XY: 2 AN XY: 686786

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000837

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 1017543). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2786 of the RYR2 protein (p.Gly2786Val). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2021

The p.G2786V variant (also known as c.8357G>T), located in coding exon 56 of the RYR2 gene, results from a G to T substitution at nucleotide position 8357. The glycine at codon 2786 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.2	D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;.
Polyphen		0.92	P;.
Vest4		0.80
MutPred		0.85		Gain of helix (P = 0.0425);.;
MVP		0.91
MPC		0.60
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.74

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: rs1060500149; hg19: chr1-237824168;