rs1553325274

chr1-237788071-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001035.3(RYR2):c.13412G>C(p.Gly4471Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,460,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4471R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.01

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 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.38354325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.13412G>C	p.Gly4471Ala	missense_variant	92/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.13412G>C	p.Gly4471Ala	missense_variant	92/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.13433G>C	p.Gly4478Ala	missense_variant	93/106
RYR2	ENST00000659194.3	c.13394G>C	p.Gly4465Ala	missense_variant	92/105
RYR2	ENST00000609119.2	c.*4504G>C		3_prime_UTR_variant, NMD_transcript_variant	91/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460118 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726114

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 08, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 488158). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4471 of the RYR2 protein (p.Gly4471Ala). -

Left ventricular noncompaction Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	23
Dann	Benign	0.85
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	0.064
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;.
REVEL	Uncertain	0.43
Sift	Benign	0.63	T;.
Polyphen		0.76	P;.
Vest4		0.35
MutPred		0.34		Gain of MoRF binding (P = 0.121);.;
MVP		0.89
MPC		1.1
ClinPred		0.62	D
GERP RS		4.5
Varity_R		0.13
gMVP		0.18

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: rs1553325274; hg19: chr1-237951371;