NM_001035.3:c.10699C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001035.3(RYR2):c.10699C>T(p.Arg3567Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000334 in 1,585,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. R3567H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: -0.0580

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: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.041636437).

BP6

Variant 1-237726282-C-T is Benign according to our data. Variant chr1-237726282-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191488.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000328 (47/1433042) while in subpopulation MID AF = 0.000175 (1/5730). AF 95% confidence interval is 0.0000392. There are 0 homozygotes in GnomAdExome4. There are 24 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 6 AD gene.

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.10699C>T	p.Arg3567Cys	missense	Exon 75 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.10699C>T	p.Arg3567Cys	missense	Exon 75 of 105	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2		c.10699C>T	p.Arg3567Cys	missense	Exon 75 of 106	ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2	TSL:5	n.*1734C>T		non_coding_transcript_exon	Exon 73 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000716

AC:

AN:

223430

AF XY:

0.0000667

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000315

Gnomad ASJ exome

AF:

0.000737

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000505

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1433042

Hom.:

Cov.:

AF XY:

0.0000337

AC XY:

AN XY:

711554

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32910

American (AMR)

AF:

0.0000236

AC:

AN:

42336

Ashkenazi Jewish (ASJ)

AF:

0.000663

AC:

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

39218

South Asian (SAS)

AF:

0.0000849

AC:

AN:

82440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52612

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1092670

Other (OTH)

AF:

0.0000672

AC:

AN:

59492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41534

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000225

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia 1 (1)

RYR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.38

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.0

PhyloP100

-0.058

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.64

REVEL

Uncertain

0.32

Sift

Benign

0.18

Polyphen

0.0

Vest4

0.066

MutPred

0.40

Loss of solvent accessibility (P = 3e-04)

MVP

0.38

MPC

0.49

ClinPred

0.029

GERP RS

-7.2

Varity_R

0.046

gMVP

0.20

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over