rs942040362

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_001035.3(RYR2):c.11116G>A(p.Asp3706Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000237 in 1,561,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D3706Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000085 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.54

Publications

3 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 -8 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=0.013501734).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000851 (12/1410708) while in subpopulation MID AF = 0.00055 (3/5450). AF 95% confidence interval is 0.000149. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.11116G>A	p.Asp3706Asn	missense_variant	Exon 80 of 105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.11116G>A	p.Asp3706Asn	missense_variant	Exon 80 of 105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.11116G>A	p.Asp3706Asn	missense_variant	Exon 80 of 106			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.*2151G>A		non_coding_transcript_exon_variant	Exon 78 of 104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000609119.2 link	n.*2151G>A		3_prime_UTR_variant	Exon 78 of 104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.000166

AC:

AN:

150606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000489

Gnomad AMI

AF:

0.0242

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:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000536

AC:

AN:

186494

AF XY:

0.0000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000851

AC:

AN:

1410708

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

697960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32380

American (AMR)

AF:

0.00

AC:

AN:

38390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25350

East Asian (EAS)

AF:

0.00

AC:

AN:

37906

South Asian (SAS)

AF:

0.00

AC:

AN:

80344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50624

Middle Eastern (MID)

AF:

0.000550

AC:

AN:

5450

European-Non Finnish (NFE)

AF:

0.00000739

AC:

AN:

1081816

Other (OTH)

AF:

0.0000171

AC:

AN:

58448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

0.000166

AC:

AN:

150606

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

73346

show subpopulations

African (AFR)

AF:

0.0000489

AC:

AN:

40872

American (AMR)

AF:

0.00

AC:

AN:

15122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10076

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67870

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.0000386

Hom.:

Bravo

AF:

0.000196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces aspartic acid with asparagine at codon 3706 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 2/217498 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:1

May 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

May 07, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as an incidental finding in a cohort of individuals referred for whole exome sequencing; however, specific clinical information about the individual(s) harboring this variant was not provided (PMID: 28404607); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 28404607, 19926015) -

Cardiovascular phenotype

Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D3706N variant (also known as c.11116G>A), located in coding exon 80 of the RYR2 gene, results from a G to A substitution at nucleotide position 11116. The aspartic acid at codon 3706 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

1.7

L;.

PhyloP100

4.5

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.8

N;.

REVEL

Uncertain

0.36

Sift

Benign

0.51

T;.

Polyphen

0.93

P;.

Vest4

0.32

MutPred

0.23

Gain of helix (P = 0.132);.;

MVP

0.94

MPC

1.2

ClinPred

0.46

GERP RS

5.0

Varity_R

0.086

gMVP

0.18

Mutation Taster

=63/37

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over