Genetic Variant RYR2:p.Met1? (chr1-237042523-T-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001035.3(RYR2):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RYR2
NM_001035.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.584

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 2
Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet
catecholaminergic polymorphic ventricular tachycardia 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 81 codons. Genomic position: 237330950. Lost 0.016 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 105	NP_001026.2	Q92736-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RYR2	ENST00000366574.7	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 105	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2		c.2T>C	p.Met1?	start_lost	Exon 1 of 106	ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2	TSL:5	n.2T>C		non_coding_transcript_exon	Exon 1 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

32366

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1103672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

522174

African (AFR)

AF:

0.00

AC:

AN:

23430

American (AMR)

AF:

0.00

AC:

AN:

9120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14418

East Asian (EAS)

AF:

0.00

AC:

AN:

27102

South Asian (SAS)

AF:

0.00

AC:

AN:

20094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4522

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

924212

Other (OTH)

AF:

0.00

AC:

AN:

44250

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.078

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.41

PhyloP100

0.58

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

Polyphen

0.0060

Vest4

0.59

MutPred

0.99

Gain of glycosylation at M1 (P = 0.0233)

MVP

0.96

ClinPred

0.68

GERP RS

3.1

PromoterAI

-0.30

Neutral

(source)

Varity_R

0.82

gMVP

0.26

Mutation Taster

=36/164

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over