1-237742270-CTTTTT-CTTTTTTT

Variant names:

• chr1-237742270-C-CTT
• rs397516499
• NM_001035.3:c.11092-12_11092-11dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001035.3(RYR2):​c.11092-12_11092-11dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,178,502 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 26)
  • Exomes 𝑓: 0.0035 (0 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580
• 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 -10 ACMG points.

• BP6: Variant 1-237742270-C-CTT is Benign according to our data. Variant chr1-237742270-C-CTT is described in ClinVar as Likely_benign. ClinVar VariationId is 1191841.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1467/138538) while in subpopulation AFR AF = 0.038 (1389/36518). AF 95% confidence interval is 0.0364. There are 29 homozygotes in GnomAd4. There are 687 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1467 AD gene.

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.11092-12_11092-11dupTT		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.11092-26_11092-25insTT		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.11092-26_11092-25insTT		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*2127-26_*2127-25insTT		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1461 AN: 138530 Hom.: 28 Cov.: 26

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00388

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000226

Gnomad FIN AF: 0.000248

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000109

Gnomad OTH AF: 0.00738

GnomAD4 exome AF: 0.00353 AC: 3670 AN: 1039964 Hom.: 0 Cov.: 0 AF XY: 0.00334 AC XY: 1732 AN XY: 519072

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

African (AFR) AF: 0.0325 AC: 758 AN: 23318

American (AMR) AF: 0.00393 AC: 92 AN: 23392

Ashkenazi Jewish (ASJ) AF: 0.00136 AC: 27 AN: 19802

East Asian (EAS) AF: 0.00149 AC: 45 AN: 30274

South Asian (SAS) AF: 0.00404 AC: 239 AN: 59118

European-Finnish (FIN) AF: 0.000910 AC: 36 AN: 39582

Middle Eastern (MID) AF: 0.00346 AC: 13 AN: 3762

European-Non Finnish (NFE) AF: 0.00286 AC: 2276 AN: 796430

Other (OTH) AF: 0.00415 AC: 184 AN: 44286

⚠️ 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: 0.0106 AC: 1467 AN: 138538 Hom.: 29 Cov.: 26 AF XY: 0.0102 AC XY: 687 AN XY: 67134

African (AFR) AF: 0.0380 AC: 1389 AN: 36518

American (AMR) AF: 0.00388 AC: 54 AN: 13920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3314

East Asian (EAS) AF: 0.00 AC: 0 AN: 4840

South Asian (SAS) AF: 0.000227 AC: 1 AN: 4402

European-Finnish (FIN) AF: 0.000248 AC: 2 AN: 8068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000109 AC: 7 AN: 64416

Other (OTH) AF: 0.00734 AC: 14 AN: 1908

Alfa AF: 0.00124 Hom.: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 07, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.058
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: rs397516499; hg19: chr1-237905570; COSMIC: COSV63722434;