rs397516516

Positions:

• chr1-237819042-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001035.3(RYR2):​c.14440A>G​(p.Met4814Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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.

• 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). 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=0.24054053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.14440A>G	p.Met4814Val	missense_variant	101/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.14440A>G	p.Met4814Val	missense_variant	101/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*5532A>G		non_coding_transcript_exon_variant	100/104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*5532A>G		3_prime_UTR_variant	100/104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 24, 2012

The Met4814Val variant in RYR2 has not been reported in the literature nor previ ously identified by our laboratory. This variant has not been identified in a ve ry large and broad population by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS). This low frequency is consistent with a disease causing role, but insufficient to establish this with confidence. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIF T) do not provide strong support for or against an impact to the protein. Additi onal information is needed to fully assess the clinical significance of the Met4 814Val variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Uncertain	0.62	D;D
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	-1.4	N;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.43
Sift	Benign	1.0	T;.
Polyphen		0.026	B;.
Vest4		0.71
MutPred		0.43		Loss of helix (P = 0.0444);.;
MVP		0.87
MPC		1.1
ClinPred		0.48	T
GERP RS		5.4
Varity_R		0.24
gMVP		0.96

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: rs397516516; hg19: chr1-237982342;