1-237742270-CTTTTT-CTTT

Variant names:

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

Variant summary

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

The NM_001035.3(RYR2):​c.11092-12_11092-11delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 1,140,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0096 (0 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580

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 1-237742270-CTT-C is Benign according to our data. Variant chr1-237742270-CTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 43704.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000166 (23/138478) while in subpopulation NFE AF= 0.000202 (13/64382). AF 95% confidence interval is 0.000119. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11092-12_11092-11delTT		intron_variant	Intron 79 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11092-25_11092-24delTT		intron_variant	Intron 79 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.1	c.898-25_898-24delTT		intron_variant	Intron 10 of 11			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*2127-25_*2127-24delTT		intron_variant	Intron 77 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.000166 AC: 23 AN: 138470 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000995

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000202

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00960 AC: 9625 AN: 1002272 Hom.: 0 AF XY: 0.00906 AC XY: 4531 AN XY: 500132

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.00761

Gnomad4 EAS exome AF: 0.00891

Gnomad4 SAS exome AF: 0.00822

Gnomad4 FIN exome AF: 0.00653

Gnomad4 NFE exome AF: 0.00968

Gnomad4 OTH exome AF: 0.00905

GnomAD4 genome AF: 0.000166 AC: 23 AN: 138478 Hom.: 0 Cov.: 26 AF XY: 0.000194 AC XY: 13 AN XY: 67088

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000995

Gnomad4 NFE AF: 0.000202

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00785 Hom.: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 06, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

11092-12_11092-11delTT in intron 79 of RYR2: This variant is not expected to hav e clinical significance because it is located outside the conserved +/- 1, 2 reg ion of the splicing consensus sequence and as part of a polyT stretch. -

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: rs397516499; hg19: chr1-237905570;