1-237801833-ATTTTT-ATTTTTTT

Variant names:

• chr1-237801833-A-ATT
• rs35563566
• NM_001035.3:c.14091-12_14091-11dupTT

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.14091-12_14091-11dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (206 hom., cov: 0)
  • Exomes 𝑓: 0.031 (149 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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-ATT is Benign according to our data. Variant chr1-237801833-A-ATT is described in ClinVar as Benign. ClinVar VariationId is 1174686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.14091-12_14091-11dupTT		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_14091-22insTT		intron_variant	Intron 97 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.14109-23_14109-22insTT		intron_variant	Intron 98 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*5183-23_*5183-22insTT		intron_variant	Intron 96 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 6960 AN: 148108 Hom.: 206 Cov.: 0

Gnomad AFR AF: 0.0903

Gnomad AMI AF: 0.0122

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0524

GnomAD2 exomes AF: 0.0360 AC: 6035 AN: 167748 AF XY: 0.0359

Gnomad AFR exome AF: 0.0859

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0353

Gnomad EAS exome AF: 0.0316

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.0319

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0314 AC: 37946 AN: 1209318 Hom.: 149 Cov.: 12 AF XY: 0.0317 AC XY: 19146 AN XY: 603888

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0788 AC: 2190 AN: 27786

American (AMR) AF: 0.0212 AC: 820 AN: 38624

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 712 AN: 22516

East Asian (EAS) AF: 0.0254 AC: 911 AN: 35896

South Asian (SAS) AF: 0.0458 AC: 3305 AN: 72132

European-Finnish (FIN) AF: 0.0179 AC: 725 AN: 40518

Middle Eastern (MID) AF: 0.0729 AC: 361 AN: 4952

European-Non Finnish (NFE) AF: 0.0296 AC: 27118 AN: 916020

Other (OTH) AF: 0.0355 AC: 1804 AN: 50874

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0470 AC: 6959 AN: 148180 Hom.: 206 Cov.: 0 AF XY: 0.0462 AC XY: 3335 AN XY: 72148

African (AFR) AF: 0.0901 AC: 3639 AN: 40410

American (AMR) AF: 0.0324 AC: 480 AN: 14834

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 99 AN: 3422

East Asian (EAS) AF: 0.0357 AC: 181 AN: 5066

South Asian (SAS) AF: 0.0406 AC: 192 AN: 4728

European-Finnish (FIN) AF: 0.0190 AC: 182 AN: 9590

Middle Eastern (MID) AF: 0.0931 AC: 27 AN: 290

European-Non Finnish (NFE) AF: 0.0305 AC: 2042 AN: 66898

Other (OTH) AF: 0.0519 AC: 106 AN: 2042

Alfa AF: 0.0210 Hom.: 457

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 28, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

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

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiomyopathy Benign:1

Dec 10, 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

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

Other links and lift over

dbSNP: rs35563566; hg19: chr1-237965133;