rs684923

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001035.3(RYR2):c.7806C>T(p.His2602His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,566,190 control chromosomes in the GnomAD database, including 172,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18079 hom., cov: 33)

Exomes 𝑓: 0.46 ( 154352 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.00800

Publications

20 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:

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=-0.37).

BP6

Variant 1-237651483-C-T is Benign according to our data. Variant chr1-237651483-C-T is described in ClinVar as Benign. ClinVar VariationId is 43827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.008 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

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.7806C>T	p.His2602His	synonymous	Exon 51 of 105	NP_001026.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR2	ENST00000366574.7	TSL:1 MANE Select	c.7806C>T	p.His2602His	synonymous	Exon 51 of 105	ENSP00000355533.2
RYR2	ENST00000661330.2		c.7806C>T	p.His2602His	synonymous	Exon 51 of 106	ENSP00000499393.2
RYR2	ENST00000609119.2	TSL:5	n.7806C>T		non_coding_transcript_exon	Exon 51 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes

AF:

0.483

AC:

73360

AN:

151846

Hom.:

18064

Cov.:

show subpopulations

Gnomad AFR

AF:

0.499

Gnomad AMI

AF:

0.407

Gnomad AMR

AF:

0.502

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.535

Gnomad FIN

AF:

0.511

Gnomad MID

AF:

0.439

Gnomad NFE

AF:

0.447

Gnomad OTH

AF:

0.492

GnomAD2 exomes

AF:

0.476

AC:

94744

AN:

198868

AF XY:

0.473

show subpopulations

Gnomad AFR exome

AF:

0.475

Gnomad AMR exome

AF:

0.504

Gnomad ASJ exome

AF:

0.300

Gnomad EAS exome

AF:

0.792

Gnomad FIN exome

AF:

0.492

Gnomad NFE exome

AF:

0.425

Gnomad OTH exome

AF:

0.450

GnomAD4 exome

AF:

0.461

AC:

651284

AN:

1414224

Hom.:

154352

Cov.:

AF XY:

0.461

AC XY:

323046

AN XY:

700806

show subpopulations

African (AFR)

AF:

0.495

AC:

16123

AN:

32582

American (AMR)

AF:

0.508

AC:

20129

AN:

39610

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

7750

AN:

25380

East Asian (EAS)

AF:

0.805

AC:

30853

AN:

38312

South Asian (SAS)

AF:

0.505

AC:

40730

AN:

80614

European-Finnish (FIN)

AF:

0.484

AC:

24954

AN:

51550

Middle Eastern (MID)

AF:

0.433

AC:

2453

AN:

5670

European-Non Finnish (NFE)

AF:

0.444

AC:

480385

AN:

1081774

Other (OTH)

AF:

0.475

AC:

27907

AN:

58732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

14819

29638

44457

59276

74095

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14732

29464

44196

58928

73660

<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:

0.483

AC:

73413

AN:

151966

Hom.:

18079

Cov.:

AF XY:

0.488

AC XY:

36275

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.499

AC:

20657

AN:

41432

American (AMR)

AF:

0.502

AC:

7664

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

1079

AN:

3468

East Asian (EAS)

AF:

0.806

AC:

4157

AN:

5156

South Asian (SAS)

AF:

0.533

AC:

2569

AN:

4824

European-Finnish (FIN)

AF:

0.511

AC:

5393

AN:

10552

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.447

AC:

30345

AN:

67950

Other (OTH)

AF:

0.495

AC:

1045

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1916

3832

5748

7664

9580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

660

1320

1980

2640

3300

<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:

0.455

Hom.:

51771

Bravo

AF:

0.484

Asia WGS

AF:

0.671

AC:

2330

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Catecholaminergic polymorphic ventricular tachycardia 1 (3)

Arrhythmogenic right ventricular dysplasia 2 (2)

not provided (2)

Cardiac arrhythmia (1)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.36

(source)

DANN

Benign

0.62

PhyloP100

0.0080

PromoterAI

-0.021

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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