1-237456575-ATTT-AT

Position:

• chr1-237456575-ATTT-AT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000366574.7(RYR2):​c.1477-12_1477-11del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,344,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 0)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: RYR2 ENST00000366574.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 1-237456575-ATT-A is Benign according to our data. Variant chr1-237456575-ATT-A is described in ClinVar as [Benign]. Clinvar id is 928598.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-237456575-ATT-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0124 (14854/1195752) while in subpopulation AMR AF= 0.0307 (745/24238). AF 95% confidence interval is 0.0289. There are 0 homozygotes in gnomad4_exome. There are 7579 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1477-12_1477-11del		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1477-12_1477-11del		intron_variant		1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000659194.3	c.1477-12_1477-11del		intron_variant				ENSP00000499653
RYR2	ENST00000660292.2	c.1477-12_1477-11del		intron_variant				ENSP00000499787
RYR2	ENST00000609119.2	c.1477-12_1477-11del		intron_variant, NMD_transcript_variant		5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.000262 AC: 39 AN: 149070 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000267

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0124 AC: 14854 AN: 1195752 Hom.: 0 AF XY: 0.0130 AC XY: 7579 AN XY: 583684

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.0307

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.00874

Gnomad4 SAS exome AF: 0.0286

Gnomad4 FIN exome AF: 0.0216

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.000268 AC: 40 AN: 149152 Hom.: 0 Cov.: 0 AF XY: 0.000386 AC XY: 28 AN XY: 72572

Gnomad4 AFR AF: 0.000147

Gnomad4 AMR AF: 0.000267

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00156

Gnomad4 NFE AF: 0.000193

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 17, 2019

Variant summary: RYR2 c.1477-12_1477-11delTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.019 in 142038 control chromosomes, predominantly at a frequency of 0.032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 533-folds over the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.1477-12_1477-11delTT in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		3.0

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: rs397516518; hg19: chr1-237619875;