rs727503402

chr1-237649869-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001035.3(RYR2):c.7513-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002575
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.270

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-237649869-T-G is Benign according to our data. Variant chr1-237649869-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165107.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.7513-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.7513-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.7513-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000660292.2	c.7513-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000609119.2	c.7513-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459426 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 06, 2014

The c.7513-8T>G variant in RYR2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant is located in t he 3' splice region. Computational tools do not suggest an impact to splicing. H owever, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.7513-8T>G variant is uncertain. -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2022

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 03, 2018

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	8.1
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0026
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.41		Position offset: 8

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503402; hg19: chr1-237813169;