rs138498780

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001035.3(RYR2):c.13983C>T(p.Tyr4661Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,610,812 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 12 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.386

Publications

2 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: Orphanet, ClinGen, G2P
catecholaminergic polymorphic ventricular tachycardia 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RYR2 links:

ENSG00000296715 (HGNC:):

ENSG00000296715 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 1-237798063-C-T is Benign according to our data. Variant chr1-237798063-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.386 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (365/152324) while in subpopulation NFE AF = 0.00367 (250/68032). AF 95% confidence interval is 0.0033. There are 0 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 365 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.13983C>T	p.Tyr4661Tyr	synonymous	Exon 97 of 105	NP_001026.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR2	ENST00000366574.7	TSL:1 MANE Select	c.13983C>T	p.Tyr4661Tyr	synonymous	Exon 97 of 105	ENSP00000355533.2
RYR2	ENST00000661330.2		c.14001C>T	p.Tyr4667Tyr	synonymous	Exon 98 of 106	ENSP00000499393.2
RYR2	ENST00000609119.2	TSL:5	n.*5075C>T		non_coding_transcript_exon	Exon 96 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00367

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00220

AC:

535

AN:

243342

AF XY:

0.00215

show subpopulations

Gnomad AFR exome

AF:

0.000531

Gnomad AMR exome

AF:

0.000651

Gnomad ASJ exome

AF:

0.000706

Gnomad EAS exome

AF:

0.000511

Gnomad FIN exome

AF:

0.00388

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00186

GnomAD4 exome

AF:

0.00283

AC:

4121

AN:

1458488

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

1981

AN XY:

725190

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33434

American (AMR)

AF:

0.000677

AC:

AN:

44292

Ashkenazi Jewish (ASJ)

AF:

0.000614

AC:

AN:

26052

East Asian (EAS)

AF:

0.000177

AC:

AN:

39614

South Asian (SAS)

AF:

0.0000936

AC:

AN:

85454

European-Finnish (FIN)

AF:

0.00334

AC:

178

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00337

AC:

3737

AN:

1110310

Other (OTH)

AF:

0.00219

AC:

132

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

191

382

572

763

954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00240

AC:

365

AN:

152324

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41580

American (AMR)

AF:

0.00176

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00321

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00367

AC:

250

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00297

Hom.:

Bravo

AF:

0.00219

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (5)

Cardiomyopathy (2)

Catecholaminergic polymorphic ventricular tachycardia 1 (2)

Arrhythmogenic right ventricular dysplasia 2 (1)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

1.8

(source)

DANN

Benign

0.53

PhyloP100

0.39

Mutation Taster

=60/40

polymorphism

(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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over