NM_001035.3:c.5400A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001035.3(RYR2):c.5400A>G(p.Lys1800Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,014 control chromosomes in the GnomAD database, including 686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 252 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 434 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.269

Publications

11 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-237614528-A-G is Benign according to our data. Variant chr1-237614528-A-G is described in ClinVar as Benign. ClinVar VariationId is 43805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.269 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 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.5400A>G	p.Lys1800Lys	synonymous	Exon 37 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.5400A>G	p.Lys1800Lys	synonymous	Exon 37 of 105	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2		c.5400A>G	p.Lys1800Lys	synonymous	Exon 37 of 106	ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2	TSL:5	n.5400A>G		non_coding_transcript_exon	Exon 37 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.0346

AC:

5268

AN:

152184

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0730

Gnomad SAS

AF:

0.0429

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0278

GnomAD2 exomes

AF:

0.0192

AC:

4792

AN:

248946

AF XY:

0.0184

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.00687

Gnomad ASJ exome

AF:

0.000696

Gnomad EAS exome

AF:

0.0819

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000727

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.00796

AC:

11630

AN:

1461712

Hom.:

434

Cov.:

AF XY:

0.00855

AC XY:

6219

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.114

AC:

3808

AN:

33480

American (AMR)

AF:

0.00807

AC:

361

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26136

East Asian (EAS)

AF:

0.0671

AC:

2662

AN:

39700

South Asian (SAS)

AF:

0.0377

AC:

3251

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000435

AC:

484

AN:

1111870

Other (OTH)

AF:

0.0160

AC:

964

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

801

1603

2404

3206

4007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.0346

AC:

5276

AN:

152302

Hom.:

252

Cov.:

AF XY:

0.0345

AC XY:

2568

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.105

AC:

4364

AN:

41554

American (AMR)

AF:

0.0145

AC:

222

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.0724

AC:

375

AN:

5180

South Asian (SAS)

AF:

0.0425

AC:

205

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68026

Other (OTH)

AF:

0.0299

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

233

466

699

932

1165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0161

Hom.:

222

Bravo

AF:

0.0383

Asia WGS

AF:

0.0670

AC:

232

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Catecholaminergic polymorphic ventricular tachycardia 1 (2)

not provided (2)

Arrhythmogenic right ventricular dysplasia 2 (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

-0.90

CADD

Benign

0.14

(source)

DANN

Benign

0.45

PhyloP100

-0.27

Mutation Taster

=97/3

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over