rs748085424

chr1-237566749-C-Achr1-237566749-C-Gchr1-237566749-C-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.3397C>A(p.Arg1133Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1133C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89

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=0.15744784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.3397C>A	p.Arg1133Ser	missense_variant	28/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.3397C>A	p.Arg1133Ser	missense_variant	28/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.3397C>A	p.Arg1133Ser	missense_variant	28/106
RYR2	ENST00000659194.3	c.3397C>A	p.Arg1133Ser	missense_variant	28/105
RYR2	ENST00000609119.2	c.3397C>A	p.Arg1133Ser	missense_variant, NMD_transcript_variant	28/104	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461658 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.27	N;.
MutationTaster	Benign	0.80	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;D
REVEL	Benign	0.060
Sift	Benign	0.79	T;T
Polyphen		0.0040	B;.
Vest4		0.52
MutPred		0.61		Gain of phosphorylation at R1133 (P = 0.0556);.;
MVP		0.65
MPC		0.43
ClinPred		0.33	T
GERP RS		3.4
Varity_R		0.11
gMVP		0.57

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: rs748085424; hg19: chr1-237730049; COSMIC: COSV63717173;