chr1-237778773-A-AAACT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_001035.3(RYR2):​c.11880+12_11880+15dupAACT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000518 in 1,352,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.153

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6
Variant 1-237778773-A-AAACT is Benign according to our data. Variant chr1-237778773-A-AAACT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1544810.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.11880+12_11880+15dupAACT intron_variant Intron 88 of 104 ENST00000366574.7 NP_001026.2 Q92736-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkc.11880+3_11880+4insAACT splice_region_variant, intron_variant Intron 88 of 104 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000661330.2 linkc.11904+3_11904+4insAACT splice_region_variant, intron_variant Intron 89 of 105 ENSP00000499393.2 A0A590UJF6
RYR2ENST00000609119.2 linkn.*2972+3_*2972+4insAACT splice_region_variant, intron_variant Intron 87 of 103 5 ENSP00000499659.2 A0A590UK06

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000404
AC:
1
AN:
247416
AF XY:
0.00
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:
0.00000892
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000518
AC:
7
AN:
1352536
Hom.:
0
Cov.:
20
AF XY:
0.00000295
AC XY:
2
AN XY:
678676
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31336
American (AMR)
AF:
0.00
AC:
0
AN:
44556
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25416
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39208
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83950
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53280
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5540
European-Non Finnish (NFE)
AF:
0.00000691
AC:
7
AN:
1012636
Other (OTH)
AF:
0.00
AC:
0
AN:
56614
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.539
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cardiomyopathy Uncertain:1
Oct 11, 2022
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant causes a duplication of four nucleotides in intron 88 of the RYR2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/247416 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. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Oct 09, 2023
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
PhyloP100
-0.15

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs773240729; hg19: chr1-237942073; API