1-237530485-G-T

Position:

• chr1-237530485-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BS1_Supporting

The NM_001035.3(RYR2):​c.2881G>T​(p.Val961Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,698 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V961G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.13

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. GenCC has associacion of the 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=0.33848926).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000275 (4/1454698) while in subpopulation MID AF= 0.000347 (2/5762). AF 95% confidence interval is 0.000061. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.2881G>T	p.Val961Leu	missense_variant	25/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.2881G>T	p.Val961Leu	missense_variant	25/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.2881G>T		non_coding_transcript_exon_variant	25/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.2881G>T	p.Val961Leu	missense_variant	25/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.2881G>T	p.Val961Leu	missense_variant	25/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454698 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 722636

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 02, 2015

The p.Val961Leu variant in RYR2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the p.Val961Leu var iant is uncertain. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 05, 2021

This missense variant replaces valine with leucine at codon 961 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 not been identified 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Benign	0.34
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.25	N;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.16	N;.
REVEL	Uncertain	0.42
Sift	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.52
MutPred		0.31		Loss of methylation at K962 (P = 0.0459);.;
MVP		0.47
MPC		0.36
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.13
gMVP		0.48

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: rs876657990; hg19: chr1-237693785; COSMIC: COSV100769131;