1-237643306-GT-GTT

Variant names:

• chr1-237643306-G-GT
• rs145140335
• NM_001035.3:c.7222-12dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.7222-12dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,565,530 control chromosomes in the GnomAD database, including 83 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (35 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.06
• Publications: 2 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 1-237643306-G-GT is Benign according to our data. Variant chr1-237643306-G-GT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1898/151552) while in subpopulation AFR AF = 0.0422 (1744/41308). AF 95% confidence interval is 0.0406. There are 48 homozygotes in GnomAd4. There are 901 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1898 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.7222-12dupT		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.7222-21_7222-20insT		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.7222-21_7222-20insT		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.7222-21_7222-20insT		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1896 AN: 151436 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00585

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00219

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.00626

GnomAD2 exomes AF: 0.00495 AC: 1041 AN: 210328 AF XY: 0.00406

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.00152

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00370

GnomAD4 exome AF: 0.00214 AC: 3028 AN: 1413978 Hom.: 35 Cov.: 30 AF XY: 0.00208 AC XY: 1460 AN XY: 702720

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

African (AFR) AF: 0.0455 AC: 1469 AN: 32258

American (AMR) AF: 0.00327 AC: 140 AN: 42764

Ashkenazi Jewish (ASJ) AF: 0.00148 AC: 37 AN: 25024

East Asian (EAS) AF: 0.00102 AC: 39 AN: 38188

South Asian (SAS) AF: 0.00227 AC: 186 AN: 81908

European-Finnish (FIN) AF: 0.00303 AC: 157 AN: 51788

Middle Eastern (MID) AF: 0.00375 AC: 21 AN: 5606

European-Non Finnish (NFE) AF: 0.000724 AC: 781 AN: 1078182

Other (OTH) AF: 0.00340 AC: 198 AN: 58260

⚠️ 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: 0.0125 AC: 1898 AN: 151552 Hom.: 48 Cov.: 32 AF XY: 0.0122 AC XY: 901 AN XY: 74056

African (AFR) AF: 0.0422 AC: 1744 AN: 41308

American (AMR) AF: 0.00584 AC: 89 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4798

European-Finnish (FIN) AF: 0.00219 AC: 23 AN: 10498

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67796

Other (OTH) AF: 0.00619 AC: 13 AN: 2100

Alfa AF: 0.00656 Hom.: 0

Bravo AF: 0.0138

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 30, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in CARDIOMYOPATHY panel(s).

Oct 29, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.7222-12dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0049 in 210328 control chromosomes, predominantly at a frequency of 0.047 within the African or African-American subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is significantly above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.7222-12dupT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

Aug 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

7222-12_7222-11insT in intron 47 of RYR2: This variant is not expected to have c linical significance because it is located outside the conserved splicing consen sus sequence.

not provided Benign:1

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Feb 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
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: rs145140335; hg19: chr1-237806606; COSMIC: COSV100767296;