1-237648523-G-C

Variant names:

• chr1-237648523-G-C
• rs121918598
• NM_001035.3:c.7422G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_001035.3(RYR2):​c.7422G>C​(p.Arg2474Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2474G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.62

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237648521-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2734117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.985
• PP5: Variant 1-237648523-G-C is Pathogenic according to our data. Variant chr1-237648523-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12955.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-237648523-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.7422G>C	p.Arg2474Ser	missense_variant	Exon 49 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.7422G>C	p.Arg2474Ser	missense_variant	Exon 49 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.7422G>C		non_coding_transcript_exon_variant	Exon 49 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.7422G>C	p.Arg2474Ser	missense_variant	Exon 49 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.7422G>C	p.Arg2474Ser	missense_variant	Exon 49 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Jan 16, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.94		Loss of sheet (P = 0.0817);.;
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.85
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs121918598; hg19: chr1-237811823;