1-237742270-CTTTTT-CTTTTTTTT

Variant names:

• chr1-237742270-C-CTTT
• rs397516499
• NM_001035.3:c.11092-13_11092-11dupTTT

Variant summary

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

The NM_001035.3(RYR2):​c.11092-13_11092-11dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00036 in 1,183,338 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 26)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: 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-C-CTTT is Benign according to our data. Variant chr1-237742270-C-CTTT is described in ClinVar as [Benign]. Clinvar id is 929110.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00104 (144/138562) while in subpopulation AFR AF= 0.00334 (122/36532). AF 95% confidence interval is 0.00286. There are 1 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 144 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11092-13_11092-11dupTTT		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.11092-26_11092-25insTTT		intron_variant	Intron 79 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.1	c.898-26_898-25insTTT		intron_variant	Intron 10 of 11			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*2127-26_*2127-25insTTT		intron_variant	Intron 77 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 140 AN: 138554 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000140

Gnomad OTH AF: 0.00158

GnomAD4 exome AF: 0.000270 AC: 282 AN: 1044776 Hom.: 0 Cov.: 0 AF XY: 0.000261 AC XY: 136 AN XY: 521446

Gnomad4 AFR exome AF: 0.00375

Gnomad4 AMR exome AF: 0.000298

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000659

Gnomad4 SAS exome AF: 0.000235

Gnomad4 FIN exome AF: 0.0000252

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.000382

GnomAD4 genome AF: 0.00104 AC: 144 AN: 138562 Hom.: 1 Cov.: 26 AF XY: 0.00118 AC XY: 79 AN XY: 67142

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000140

Gnomad4 OTH AF: 0.00157

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 15, 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.11092-13_11092-11dupTTT duplicates three Ts in a polyT region located close to a canonical splice site. 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 0.0013 in 24260 control chromosomes. The observed variant frequency is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.11092-13_11092-11dupTTT in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with a pathogenic variant has been reported (PKP2 c.2197_2202delinsG, p.His733fsX8, internal sample), providing supporting evidence for a benign role. 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

Splicing

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;