rs72027983

Positions:

• chr1-237801833-A-AT
• chr1-237801833-AT-A
• chr1-237801833-A-ATTTTTTTT
• chr1-237801833-A-ATT
• chr1-237801833-ATT-A
• chr1-237801833-A-ATTT
• chr1-237801833-A-ATTTTTTTTT
• chr1-237801833-A-ATTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.14091-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9157 hom., cov: 0)
  • Exomes 𝑓: 0.31 (11321 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.362

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-237801833-A-AT is Benign according to our data. Variant chr1-237801833-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 43736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.14091-11dupT		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.14091-11dupT		intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*5183-11dupT		intron_variant		5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 51992 AN: 147984 Hom.: 9154 Cov.: 0

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.337

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.354

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.308 AC: 365662 AN: 1186704 Hom.: 11321 Cov.: 12 AF XY: 0.308 AC XY: 182363 AN XY: 592688

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.339

Gnomad4 EAS exome AF: 0.411

Gnomad4 SAS exome AF: 0.302

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.313

GnomAD4 genome AF: 0.351 AC: 52020 AN: 148058 Hom.: 9157 Cov.: 0 AF XY: 0.352 AC XY: 25369 AN XY: 72076

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.575

Gnomad4 SAS AF: 0.385

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 28, 2011	14091-11_14091-10insT in intron 97 of RYR2: This variant is not expected to have clinical significance because it is located outside the conserved +/- 1, 2 regi on of the splicing consensus sequence and as part of a polyT stretch. This vari ant has been reported in dbSNP (rs72027983 & rs55683196) without frequency infor mation. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2018	Variant summary: The RYR2 c.14091-11dupT variant involves the alteration of an intronic nucleotide in a poly-T stretch. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 10364/27792 control chromosomes (1716 homozygotes)in gnomAD at a frequency of 0.3729131, which is approximately 6780 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. In addition, one laboratory classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 30, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs35563566; hg19: chr1-237965133;