1-237456575-ATTTT-ATTTTTTTT

Variant names:

• chr1-237456575-A-ATTTT
• rs397516518
• NM_001035.3:c.1477-14_1477-11dupTTTT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001035.3(RYR2):​c.1477-14_1477-11dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Likely 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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 1-237456575-A-ATTTT is Benign according to our data. Variant chr1-237456575-A-ATTTT is described in ClinVar as [Likely_benign]. Clinvar id is 918143.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1477-14_1477-11dupTTTT		intron_variant	Intron 15 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1477-25_1477-24insTTTT		intron_variant	Intron 15 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1477-25_1477-24insTTTT		intron_variant	Intron 15 of 103	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1477-25_1477-24insTTTT		intron_variant	Intron 15 of 105			ENSP00000499787.2
RYR2	ENST00000659194.3	c.1477-25_1477-24insTTTT		intron_variant	Intron 15 of 104			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000657 AC: 8 AN: 1216926 Hom.: 0 Cov.: 0 AF XY: 0.0000118 AC XY: 7 AN XY: 593934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000310

Gnomad4 SAS exome AF: 0.0000393

Gnomad4 FIN exome AF: 0.0000263

Gnomad4 NFE exome AF: 0.00000309

Gnomad4 OTH exome AF: 0.0000203

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 30, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.1477-14_1477-11dupTTTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 142038 control chromosomes, however there are several other duplicaton and deletions of the polyT tract present in gnomad at a high frequency, suggesting the benign nature of the variant. To our knowledge, no occurrence of c.1477-14_1477-11dupTTTT in individuals affected with Cardiomyopathy 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 likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		3.0

Splicing

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;