1-237649983-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4 BP6 BS1 BS2

The NM_001035.3(RYR2):c.7619A>G(p.His2540Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,986 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. H2540Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 2.38

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.31440914).
• BP6: Variant 1-237649983-A-G is Benign according to our data. Variant chr1-237649983-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43826.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4, Benign=2}. Variant chr1-237649983-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000617 (94/152302) while in subpopulation AFR AF= 0.00212 (88/41584). AF 95% confidence interval is 0.00176. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.7619A>G	p.His2540Arg	missense_variant	50/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.7619A>G	p.His2540Arg	missense_variant	50/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.7619A>G	p.His2540Arg	missense_variant	50/106
RYR2	ENST00000659194.3	c.7619A>G	p.His2540Arg	missense_variant	50/105
RYR2	ENST00000609119.2	c.7619A>G	p.His2540Arg	missense_variant, NMD_transcript_variant	50/104	5

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000144 AC: 36 AN: 249296 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135244

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 727132

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74472

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000767

ESP6500AA AF: 0.00172 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000141 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 30, 2013	Variant classified as Uncertain Significance - Favor Benign. The His2540Arg vari ant in RYR2 has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 0.2% (7/4062) of African Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200105499). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT ) do not provide strong support for or against an impact to the protein. In summ ary, although the frequency of this variant suggests that it is more likely beni gn, it is too low to confidently rule out a disease-causing role and additional information is needed to fully assess its clinical significance. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2018	Variant summary: RYR2 c.7619A>G (p.His2540Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 277206 control chromosomes, predominantly at a frequency of 0.0021 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 84 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.7619A>G has been reported in the literature in individuals affected with Cardiomyopathy (Landstrom_2017, Mademon-Soler_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 27, 2018	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2022

Reported in an adult with HCM who also harbored additional cardiogenetic variants (Mademont-Soler et al., 2017); 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 (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 28771489, 19926015, 28404607) -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

RYR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2021

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	0.18
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-6.1	D;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D;.
Polyphen		0.99	D;.
Vest4		0.46
MVP		0.86
MPC		0.94
ClinPred		0.18	T
GERP RS		5.6
Varity_R		0.72
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs200105499; hg19: chr1-237813283;