1-237801833-ATTTTT-ATTTTTT

Variant names:

• chr1-237801833-A-AT
• rs35563566
• NM_001035.3:c.14091-11dupT

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.14091-11dupT		intron_variant	Intron 97 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.14091-23_14091-22insT		intron_variant	Intron 97 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.14109-23_14109-22insT		intron_variant	Intron 98 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*5183-23_*5183-22insT		intron_variant	Intron 96 of 103	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

GnomAD2 exomes AF: 0.347 AC: 58211 AN: 167748 AF XY: 0.347

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.370

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.334

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

African (AFR) AF: 0.266 AC: 7300 AN: 27410

American (AMR) AF: 0.266 AC: 10073 AN: 37810

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 7503 AN: 22148

East Asian (EAS) AF: 0.411 AC: 14592 AN: 35466

South Asian (SAS) AF: 0.302 AC: 21548 AN: 71306

European-Finnish (FIN) AF: 0.310 AC: 12315 AN: 39754

Middle Eastern (MID) AF: 0.336 AC: 1651 AN: 4908

European-Non Finnish (NFE) AF: 0.306 AC: 275066 AN: 897998

Other (OTH) AF: 0.313 AC: 15614 AN: 49904

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

African (AFR) AF: 0.301 AC: 12168 AN: 40384

American (AMR) AF: 0.315 AC: 4669 AN: 14828

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1450 AN: 3420

East Asian (EAS) AF: 0.575 AC: 2908 AN: 5056

South Asian (SAS) AF: 0.385 AC: 1815 AN: 4716

European-Finnish (FIN) AF: 0.389 AC: 3726 AN: 9570

Middle Eastern (MID) AF: 0.334 AC: 97 AN: 290

European-Non Finnish (NFE) AF: 0.361 AC: 24129 AN: 66852

Other (OTH) AF: 0.356 AC: 727 AN: 2042

Alfa AF: 0.226 Hom.: 457

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 12, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 28, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiomyopathy Benign:1

Sep 30, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35563566; hg19: chr1-237965133;