rs200450676

chr1-237595526-T-Achr1-237595526-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001035.3(RYR2):c.4465T>A(p.Cys1489Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1489R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.01

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4465T>A	p.Cys1489Ser	missense_variant	34/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4465T>A	p.Cys1489Ser	missense_variant	34/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.4465T>A	p.Cys1489Ser	missense_variant	34/106
RYR2	ENST00000659194.3	c.4465T>A	p.Cys1489Ser	missense_variant	34/105
RYR2	ENST00000609119.2	c.4465T>A	p.Cys1489Ser	missense_variant, NMD_transcript_variant	34/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Uncertain	0.32
Sift	Benign	0.13	T;.
Polyphen		0.0070	B;.
Vest4		0.77
MutPred		0.69		Gain of disorder (P = 0.0017);.;
MVP		0.42
MPC		0.81
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.40		Position offset: -28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200450676; hg19: chr1-237758826;