rs749607906

chr1-237506711-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_001035.3(RYR2):c.2615T>C(p.Ile872Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,453,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I872I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense, splice_region
• Scores: Splicing: ADA: 0.4643
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.02

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.2615T>C	p.Ile872Thr	missense_variant, splice_region_variant	23/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.2615T>C	p.Ile872Thr	missense_variant, splice_region_variant	23/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.2615T>C	p.Ile872Thr	missense_variant, splice_region_variant	23/106
RYR2	ENST00000659194.3	c.2615T>C	p.Ile872Thr	missense_variant, splice_region_variant	23/105
RYR2	ENST00000609119.2	c.2615T>C	p.Ile872Thr	missense_variant, splice_region_variant, NMD_transcript_variant	23/104	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000247 AC: 6 AN: 242612 Hom.: 0 AF XY: 0.0000228 AC XY: 3 AN XY: 131302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000619 AC: 9 AN: 1453984 Hom.: 0 Cov.: 30 AF XY: 0.00000553 AC XY: 4 AN XY: 722888

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: 0.00000812

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2019

In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs749607906, ExAC 0.009%) but has not been reported in the literature in individuals with a RYR2-related disease. This sequence change replaces isoleucine with threonine at codon 872 of the RYR2 protein (p.Ile872Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2022

The p.I872T variant (also known as c.2615T>C), located in coding exon 23 of the RYR2 gene, results from a T to C substitution at nucleotide position 2615. The isoleucine at codon 872 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.86
Sift	Benign	0.25	T;.
Polyphen		0.99	D;.
Vest4		0.93
MutPred		0.64		Gain of disorder (P = 0.0308);.;
MVP		0.92
MPC		1.2
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.46
dbscSNV1_RF	Benign	0.32
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: rs749607906; hg19: chr1-237670011;