1-237801833-ATTTTT-ATTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001035.3(RYR2):​c.14091-12_14091-11delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,354,864 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (0 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: 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: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.14091-12_14091-11delTT		intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.14091-22_14091-21delTT		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.14109-22_14109-21delTT		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*5183-22_*5183-21delTT		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148140 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00143 AC: 240 AN: 167748 AF XY: 0.00132

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00259

Gnomad ASJ exome AF: 0.00112

Gnomad EAS exome AF: 0.000760

Gnomad FIN exome AF: 0.00118

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.00131 AC: 1575 AN: 1206654 Hom.: 0 AF XY: 0.00138 AC XY: 832 AN XY: 602628

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

African (AFR) AF: 0.00115 AC: 32 AN: 27868

American (AMR) AF: 0.00222 AC: 85 AN: 38332

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 28 AN: 22494

East Asian (EAS) AF: 0.000305 AC: 11 AN: 36052

South Asian (SAS) AF: 0.00209 AC: 151 AN: 72112

European-Finnish (FIN) AF: 0.00114 AC: 46 AN: 40500

Middle Eastern (MID) AF: 0.000603 AC: 3 AN: 4976

European-Non Finnish (NFE) AF: 0.00127 AC: 1160 AN: 913470

Other (OTH) AF: 0.00116 AC: 59 AN: 50850

⚠️ 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: 0.00000675 AC: 1 AN: 148210 Hom.: 0 Cov.: 0 AF XY: 0.0000139 AC XY: 1 AN XY: 72162

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

African (AFR) AF: 0.00 AC: 0 AN: 40428

American (AMR) AF: 0.00 AC: 0 AN: 14840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66902

Other (OTH) AF: 0.00 AC: 0 AN: 2042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00393 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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;