rs377293019

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001035.3(RYR2):c.12492G>A(p.Gln4164Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,613,904 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.57

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:

ENSG00000296715 (HGNC:):

ENSG00000296715 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 1-237784204-G-A is Benign according to our data. Variant chr1-237784204-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201183.

BP7

Synonymous conserved (PhyloP=3.57 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000223 (34/152202) while in subpopulation NFE AF = 0.000426 (29/68050). AF 95% confidence interval is 0.000304. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 34 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.12492G>A	p.Gln4164Gln	synonymous	Exon 90 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.12492G>A	p.Gln4164Gln	synonymous	Exon 90 of 105	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2		c.12516G>A	p.Gln4172Gln	synonymous	Exon 91 of 106	ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2	TSL:5	n.*3584G>A		non_coding_transcript_exon	Exon 89 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000193

AC:

AN:

248842

AF XY:

0.000178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000382

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000354

AC:

517

AN:

1461702

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

229

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000436

AC:

485

AN:

1111862

Other (OTH)

AF:

0.000331

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000223

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68050

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000426

Hom.:

Bravo

AF:

0.000223

EpiCase

AF:

0.000109

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Catecholaminergic polymorphic ventricular tachycardia 1 (2)

not specified (2)

Arrhythmogenic right ventricular dysplasia 2 (1)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.5

(source)

DANN

Benign

0.68

PhyloP100

3.6

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over