1-237643306-GT-GTT

Position:

• chr1-237643306-GT-GTT

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: 2.06

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1898 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.7222-12dupT		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.7222-12dupT		intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.7222-12dupT		intron_variant		5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.7222-12dupT		intron_variant				ENSP00000499787.2
RYR2	ENST00000659194.3	c.7222-12dupT		intron_variant				ENSP00000499653.3

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

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

Gnomad4 AFR exome AF: 0.0455

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.00148

Gnomad4 EAS exome AF: 0.00102

Gnomad4 SAS exome AF: 0.00227

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.000724

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.0125 AC: 1898 AN: 151552 Hom.: 48 Cov.: 32 AF XY: 0.0122 AC XY: 901 AN XY: 74056

Gnomad4 AFR AF: 0.0422

Gnomad4 AMR AF: 0.00584

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.00219

Gnomad4 NFE AF: 0.000339

Gnomad4 OTH AF: 0.00619

Bravo AF: 0.0138

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2014	The variant is found in CARDIOMYOPATHY panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 14, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2019	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs145140335; hg19: chr1-237806606;