1-237590668-G-T

Position:

• chr1-237590668-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001035.3(RYR2):​c.3836G>T​(p.Ser1279Ile) 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. 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. S1279T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23

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]

RYR2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.3836G>T	p.Ser1279Ile	missense_variant	31/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.3836G>T	p.Ser1279Ile	missense_variant	31/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.3836G>T		non_coding_transcript_exon_variant	31/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.3836G>T	p.Ser1279Ile	missense_variant	31/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.3836G>T	p.Ser1279Ile	missense_variant	31/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;T
Eigen	Benign	-0.039
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.74	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.017	D;.
Polyphen		0.097	B;.
Vest4		0.84
MutPred		0.61		Loss of disorder (P = 0.0371);.;
MVP		0.92
MPC		0.50
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.24
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs751419465; hg19: chr1-237753968;