chr1-237623771-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2

The NM_001035.3(RYR2):ā€‹c.5923A>Gā€‹(p.Met1975Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 1,600,700 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. M1975I) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 31)
Exomes š‘“: 0.000030 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

3
8
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 9.29
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
BP4
Computational evidence support a benign effect (MetaRNN=0.2717461).
BP6
Variant 1-237623771-A-G is Benign according to our data. Variant chr1-237623771-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191483.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=5}.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000297 (43/1448572) while in subpopulation MID AF= 0.000175 (1/5726). AF 95% confidence interval is 0.0000335. There are 0 homozygotes in gnomad4_exome. There are 29 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.5923A>G p.Met1975Val missense_variant Exon 39 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.5923A>G p.Met1975Val missense_variant Exon 39 of 105 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000609119.2 linkn.5923A>G non_coding_transcript_exon_variant Exon 39 of 104 5 ENSP00000499659.2 A0A590UK06
RYR2ENST00000660292.2 linkc.5923A>G p.Met1975Val missense_variant Exon 39 of 106 ENSP00000499787.2 A0A590UKB7
RYR2ENST00000659194.3 linkc.5923A>G p.Met1975Val missense_variant Exon 39 of 105 ENSP00000499653.3 A0A590UJZ8

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152010
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000607
AC:
15
AN:
247224
Hom.:
0
AF XY:
0.0000821
AC XY:
11
AN XY:
133998
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000801
Gnomad EAS exome
AF:
0.000168
Gnomad SAS exome
AF:
0.0000336
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000297
AC:
43
AN:
1448572
Hom.:
0
Cov.:
27
AF XY:
0.0000402
AC XY:
29
AN XY:
721398
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.000500
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000352
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000118
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152128
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000745
AC:
9
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jul 31, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported in individuals with atrial fibrillation or LVNC as well as in a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death who underwent exome sequencing (PMID: 31539150, 33500567, 23861362); In silico analysis supports that this missense variant has a deleterious effect on 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: 32508047, 33500567, 19926015, 31539150, 23861362) -

-
Clinical Genetics, Academic Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:1
Feb 10, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Met1975Val variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/66168 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s200318013). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Met1975Val variant is uncertain. -

Nov 07, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: RYR2 c.5923A>G (p.Met1975Val) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 247224 control chromosomes. The observed variant frequency is approximately 1.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), suggesting that the variant is benign. c.5923A>G has been reported in the literature in individuals affected with atrial fibrilation in which the variant did not segregate with disease (Maltese_2019), in a patient with left ventricular noncompaction without strong evidence for causality (Mazzarotto_2020), and in healthy controls (Luo_2020). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: two classified as likely benign while four classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy Benign:2
Mar 21, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 13, 2017
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Conduction disorder of the heart Uncertain:1
Dec 16, 2019
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Dec 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Jun 27, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Benign
-0.085
T
BayesDel_noAF
Benign
-0.10
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.86
D;T
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.6
M;.
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.2
D;.
REVEL
Uncertain
0.40
Sift
Uncertain
0.024
D;.
Polyphen
0.024
B;.
Vest4
0.75
MutPred
0.43
Loss of disorder (P = 0.0606);.;
MVP
0.81
MPC
0.38
ClinPred
0.21
T
GERP RS
5.3
Varity_R
0.34
gMVP
0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200318013; hg19: chr1-237787071; API