1-237491919-C-T

Position:

chr1-237491919-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 3P and 11B. PM1PP2BP4_ModerateBP6BS1BS2

The NM_001035.3(RYR2):c.1822C>T(p.His608Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000792 in 1,225,470 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H608D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 5.03

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 Benign. Variant got -8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001035.3

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=0.19025978).

BP6

Variant 1-237491919-C-T is Benign according to our data. Variant chr1-237491919-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179220.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000401 (61/152198) while in subpopulation AFR AF= 0.00142 (59/41450). AF 95% confidence interval is 0.00113. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.1822C>T	p.His608Tyr	missense_variant	18/105	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.1822C>T	p.His608Tyr	missense_variant	18/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 linkuse as main transcript	n.1822C>T		non_coding_transcript_exon_variant	18/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 linkuse as main transcript	c.1822C>T	p.His608Tyr	missense_variant	18/106			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 linkuse as main transcript	c.1822C>T	p.His608Tyr	missense_variant	18/105			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000724

AC:

AN:

152008

Hom.:

AF XY:

0.0000877

AC XY:

AN XY:

79780

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.0000445

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1073272

Hom.:

Cov.:

AF XY:

0.0000369

AC XY:

AN XY:

542642

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.0000302

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:

0.00

Gnomad4 OTH exome

AF:

0.000170

GnomAD4 genome

AF:

0.000401

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000229

Hom.:

Bravo

AF:

0.000457

ExAC

AF:

0.0000552

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2024	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 19926015) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 25, 2019	- -

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 04, 2018	Variant summary: RYR2 c.1822C>T (p.His608Tyr) results in a conservative amino acid change located in the RIH and B30.2/SPRY domains of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 178558 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0019 in the gnomAD database. This frequency within African control individuals is approximately 76-fold above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.1822C>T, has been reported in the literature in individuals affected with Cardiomyopathy without evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with classifications of uncertain significance (2x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 10, 2013	The His608Tyr variant in RYR2 has not been reported in individuals with cardiomy opathy and data from large population studies is insufficient to assess the freq uency of this variant. Computational analyses (biochemical amino acid properties , conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support fo r or against an impact to the protein, though 1 fish (stickleback) carries a tyr osine (Tyr; this variant), raising the possibility that the change may be tolera ted. Additional information is needed to fully assess the clinical significance of the His608Tyr variant. -

Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Apr 27, 2016

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 26, 2018

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2020

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

0.19

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.19

T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.7

L;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.8

D;.

REVEL

Uncertain

0.54

Sift

Benign

0.11

T;.

Polyphen

0.0020

B;.

Vest4

0.36

MVP

0.96

MPC

0.46

ClinPred

0.10

GERP RS

6.0

Varity_R

0.32

gMVP

0.75

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

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