chr1-237500871-C-A

Position:

chr1-237500871-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_001035.3(RYR2):c.2364C>A(p.Phe788Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.98

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.2364C>A	p.Phe788Leu	missense_variant	21/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.2364C>A	p.Phe788Leu	missense_variant	21/105	1	NM_001035.3	ENSP00000355533	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.2364C>A	p.Phe788Leu	missense_variant	21/106			ENSP00000499787
RYR2	ENST00000659194.3 linkuse as main transcript	c.2364C>A	p.Phe788Leu	missense_variant	21/105			ENSP00000499653
RYR2	ENST00000609119.2 linkuse as main transcript	c.2364C>A	p.Phe788Leu	missense_variant, NMD_transcript_variant	21/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249286

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135238

show subpopulations

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727134

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 18, 2018

The p.Phe788Leu variant (rs776018906) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.001 percent (identified on 3 out of 246,232 chromosomes). The phenylalanine at position 788 is highly conserved considering 10 species (Alamut v2.11) and computational analyses of the p.Phe788Leu variant on protein structure and function indicates a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Phe788Leu variant with certainty. -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2021

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: 576435). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs776018906, ExAC 0.004%). This sequence change replaces phenylalanine with leucine at codon 788 of the RYR2 protein (p.Phe788Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2021

The p.F788L variant (also known as c.2364C>A), located in coding exon 21 of the RYR2 gene, results from a C to A substitution at nucleotide position 2364. The phenylalanine at codon 788 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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

Pathogenic

0.93

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.6

D;.

REVEL

Uncertain

0.35

Sift

Benign

0.083

T;.

Polyphen

0.87

P;.

Vest4

0.89

MutPred

0.79

Loss of sheet (P = 0.1398);.;

MVP

0.49

MPC

0.44

ClinPred

0.95

GERP RS

5.1

Varity_R

0.47

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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