chr1-237792141-C-T

Position:

chr1-237792141-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001035.3(RYR2):c.13600C>T(p.Pro4534Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,454,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 1.26

Variant links:

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 links:

RYR2 (HGNC:):

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.10589728).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.13600C>T	p.Pro4534Ser	missense_variant	94/105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.13600C>T	p.Pro4534Ser	missense_variant	94/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 linkuse as main transcript	n.*4692C>T		non_coding_transcript_exon_variant	93/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000609119.2 linkuse as main transcript	n.*4692C>T		3_prime_UTR_variant	93/104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000464

AC:

AN:

237172

Hom.:

AF XY:

0.0000312

AC XY:

AN XY:

128226

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000561

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1454876

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

722878

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000916

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000731

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000496

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2015	p.Pro4534Ser (CCC>TCC): c.13600 C>T in exon 94 of the RYR2 gene (NM_001035.2). The Pro4534Ser variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro4534Ser was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Pro4534Ser results in a non-conservative amino acid substitution of a non-polar Proline with a polar Serine at a position that is not well conserved across species, but is located in one of three mutation hot spot regions in the RYR2 gene (Medeiros- Domingo A et al., 2009). Nevertheless, in-silico analysis programs predict Pro4534Ser is benign to the protein structure/function. We cannot definitively determine if Pro4534Ser is a disease-causing mutation or a rare benign variant. The variant is found in POSTMORTEM panel(s). -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jun 01, 2015

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro4534Ser (c.13600C>T) in the RYR2 gene (NM_001035) Given the lack of case data and lack of ancestry-matched controls, we consider this variant a variant of uncertain significance. I could find no report of the variant in association with disease. It is not listed in ClinVar (as of July 8th, 2014). Per Ng et al (2013) it is not listed in HGMD or any LSDB they checked. In silico analysis with PolyPhen-2 predicts the variant to be benign. The proline at codon 4534 is conserved across species. In total the variant has been seen in 1 of 7009 individuals from publicly available population datasets. There is no variation at codon 4534 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 8th, 2014). The variant was seen in 1 of 509 individuals in the ClinSeq project (Ng et al 2013), a sample not selected for arrhythmia or family history of sudden death (3.7% were Hispanic). Note that this dataset does not match the patient's ancestry (Hispanic). The variant is listed in dbSNP with the only submission being the ClinSeq data (rs199624074). -

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2023

This missense variant replaces proline with serine at codon 4534 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual afflicted with unspecified cardiomyopathy (PMID: 30847666). This variant has been identified in 11/237172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 02, 2022

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.48

T;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.95

L;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.24

Sift

Benign

0.83

T;.

Polyphen

0.0050

B;.

Vest4

0.15

MutPred

0.48

Gain of phosphorylation at P4534 (P = 0.0145);.;

MVP

0.46

MPC

0.89

ClinPred

0.042

GERP RS

3.5

Varity_R

0.043

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over