rs727505149

chr1-237589850-A-C

Variant summary

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

The NM_001035.3(RYR2):c.3656A>C(p.Lys1219Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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.3656A>C	p.Lys1219Thr	missense_variant	30/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.3656A>C	p.Lys1219Thr	missense_variant	30/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.3656A>C	p.Lys1219Thr	missense_variant	30/106
RYR2	ENST00000659194.3	c.3656A>C	p.Lys1219Thr	missense_variant	30/105
RYR2	ENST00000609119.2	c.3656A>C	p.Lys1219Thr	missense_variant, NMD_transcript_variant	30/104	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Jun 30, 2014

The Lys1219Thr variant in RYR2 has not been previously reported in individuals w ith 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 Lys1219Thr var iant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.34
Sift	Benign	0.15	T;.
Polyphen		0.19	B;.
Vest4		0.76
MutPred		0.60		Loss of ubiquitination at K1219 (P = 0.0174);.;
MVP		0.75
MPC		0.55
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.19
gMVP		0.84

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: rs727505149; hg19: chr1-237753150;