rs121918599

chr1-237784024-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001035.3(RYR2):c.12312C>G(p.Asn4104Lys) 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. N4104I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0990

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 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237784023-A-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 1-237784024-C-G is Pathogenic according to our data. Variant chr1-237784024-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 12956.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-237784024-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.12312C>G	p.Asn4104Lys	missense_variant	90/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.12312C>G	p.Asn4104Lys	missense_variant	90/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.12333C>G	p.Asn4111Lys	missense_variant	91/106
RYR2	ENST00000659194.3	c.12300C>G	p.Asn4100Lys	missense_variant	90/105
RYR2	ENST00000609119.2	c.*3404C>G		3_prime_UTR_variant, NMD_transcript_variant	89/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 16, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	9.1
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.99	A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.87		Gain of ubiquitination at N4104 (P = 0.0408);.;
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		-1.8
Varity_R		0.62
gMVP		0.97

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: rs121918599; hg19: chr1-237947324;