1-237801833-ATTTTT-ATTTTTTTT

Variant names:

• chr1-237801833-A-ATTT
• rs35563566
• NM_001035.3:c.14091-13_14091-11dupTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001035.3(RYR2):​c.14091-13_14091-11dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0060 (19 hom., cov: 0)
  • Exomes 𝑓: 0.0054 (33 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: ClinGen, G2P, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.14091-13_14091-11dupTTT		intron	N/A	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.14091-23_14091-22insTTT		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.14109-23_14109-22insTTT		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*5183-23_*5183-22insTTT		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 890 AN: 148148 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.000769

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00560

Gnomad ASJ AF: 0.00409

Gnomad EAS AF: 0.000590

Gnomad SAS AF: 0.0771

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.00483

Gnomad OTH AF: 0.00743

GnomAD2 exomes AF: 0.00777 AC: 1303 AN: 167748 AF XY: 0.00933

Gnomad AFR exome AF: 0.00227

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00251

Gnomad EAS exome AF: 0.000456

Gnomad FIN exome AF: 0.00281

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00537 AC: 6528 AN: 1216664 Hom.: 33 Cov.: 12 AF XY: 0.00651 AC XY: 3953 AN XY: 607552

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

African (AFR) AF: 0.00157 AC: 44 AN: 28106

American (AMR) AF: 0.00191 AC: 74 AN: 38806

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 72 AN: 22652

East Asian (EAS) AF: 0.000304 AC: 11 AN: 36174

South Asian (SAS) AF: 0.0445 AC: 3222 AN: 72404

European-Finnish (FIN) AF: 0.00415 AC: 169 AN: 40746

Middle Eastern (MID) AF: 0.0228 AC: 113 AN: 4966

European-Non Finnish (NFE) AF: 0.00271 AC: 2500 AN: 921612

Other (OTH) AF: 0.00631 AC: 323 AN: 51198

⚠️ 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: 0.00602 AC: 892 AN: 148218 Hom.: 19 Cov.: 0 AF XY: 0.00711 AC XY: 513 AN XY: 72164

African (AFR) AF: 0.000767 AC: 31 AN: 40430

American (AMR) AF: 0.00559 AC: 83 AN: 14842

Ashkenazi Jewish (ASJ) AF: 0.00409 AC: 14 AN: 3422

East Asian (EAS) AF: 0.000592 AC: 3 AN: 5068

South Asian (SAS) AF: 0.0777 AC: 367 AN: 4726

European-Finnish (FIN) AF: 0.00500 AC: 48 AN: 9596

Middle Eastern (MID) AF: 0.0276 AC: 8 AN: 290

European-Non Finnish (NFE) AF: 0.00483 AC: 323 AN: 66904

Other (OTH) AF: 0.00735 AC: 15 AN: 2040

Alfa AF: 0.00291 Hom.: 457

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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;