rs727504792

chr1-237614767-A-Cchr1-237614767-A-T

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.5639A>C(p.Glu1880Ala) 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. 14/21 in silico tools predict a benign outcome for this variant. 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. E1880V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.2000634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.5639A>C	p.Glu1880Ala	missense_variant	37/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.5639A>C	p.Glu1880Ala	missense_variant	37/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.5639A>C	p.Glu1880Ala	missense_variant	37/106
RYR2	ENST00000659194.3	c.5639A>C	p.Glu1880Ala	missense_variant	37/105
RYR2	ENST00000609119.2	c.5639A>C	p.Glu1880Ala	missense_variant, NMD_transcript_variant	37/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Uncertain	0.66	D;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.18
Sift	Benign	0.17	T;.
Polyphen		0.018	B;.
Vest4		0.25
MutPred		0.20		Loss of solvent accessibility (P = 0.0224);.;
MVP		0.74
MPC		0.38
ClinPred		0.15	T
GERP RS		2.0
Varity_R		0.093
gMVP		0.26

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: rs727504792; hg19: chr1-237778067;