NM_001035.3:c.2772G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_001035.3(RYR2):​c.2772G>T​(p.Leu924Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,567,636 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L924L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 29)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RYR2
NM_001035.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.551

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.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
Variant 1-237511741-G-T is Benign according to our data. Variant chr1-237511741-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1559699.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-0.551 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.2772G>T p.Leu924Leu synonymous_variant Exon 24 of 105 ENST00000366574.7 NP_001026.2 Q92736-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkc.2772G>T p.Leu924Leu synonymous_variant Exon 24 of 105 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000661330.2 linkc.2772G>T p.Leu924Leu synonymous_variant Exon 24 of 106 ENSP00000499393.2 A0A590UJF6
RYR2ENST00000609119.2 linkn.2772G>T non_coding_transcript_exon_variant Exon 24 of 104 5 ENSP00000499659.2 A0A590UK06

Frequencies

GnomAD3 genomes
AF:
0.00000668
AC:
1
AN:
149664
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
199044
AF XY:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000141
AC:
2
AN:
1417972
Hom.:
0
Cov.:
31
AF XY:
0.00000285
AC XY:
2
AN XY:
701794
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32816
American (AMR)
AF:
0.00
AC:
0
AN:
39818
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25094
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38312
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80212
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50964
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5674
European-Non Finnish (NFE)
AF:
0.00000184
AC:
2
AN:
1086542
Other (OTH)
AF:
0.00
AC:
0
AN:
58540
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000668
AC:
1
AN:
149664
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
72656
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
40790
American (AMR)
AF:
0.00
AC:
0
AN:
14744
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3462
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5028
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4760
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9878
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
310
European-Non Finnish (NFE)
AF:
0.0000148
AC:
1
AN:
67734
Other (OTH)
AF:
0.00
AC:
0
AN:
2050
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Dec 08, 2024
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
BayesDel_noAF
Benign
-0.55
CADD
Benign
3.5
DANN
Benign
0.76
PhyloP100
-0.55
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs780664060; hg19: chr1-237675041; API