1-237742270-CTTTTT-CTTTTTTTTT

Variant names:

• chr1-237742270-C-CTTTT
• rs397516499
• NM_001035.3:c.11092-14_11092-11dupTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001035.3(RYR2):​c.11092-14_11092-11dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,183,802 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-237742270-C-CTTTT is Benign according to our data. Variant chr1-237742270-C-CTTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 928595.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.11092-14_11092-11dupTTTT		intron	N/A	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.11092-26_11092-25insTTTT		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.11092-26_11092-25insTTTT		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*2127-26_*2127-25insTTTT		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0000144 AC: 2 AN: 138556 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000527

GnomAD4 exome AF: 0.0000220 AC: 23 AN: 1045246 Hom.: 0 Cov.: 0 AF XY: 0.0000211 AC XY: 11 AN XY: 521698

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000255 AC: 6 AN: 23502

American (AMR) AF: 0.0000851 AC: 2 AN: 23504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19862

East Asian (EAS) AF: 0.00 AC: 0 AN: 30358

South Asian (SAS) AF: 0.0000168 AC: 1 AN: 59496

European-Finnish (FIN) AF: 0.0000252 AC: 1 AN: 39674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3780

European-Non Finnish (NFE) AF: 0.0000162 AC: 13 AN: 800558

Other (OTH) AF: 0.00 AC: 0 AN: 44512

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000013467), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000144 AC: 2 AN: 138556 Hom.: 0 Cov.: 26 AF XY: 0.0000149 AC XY: 1 AN XY: 67112

African (AFR) AF: 0.0000274 AC: 1 AN: 36474

American (AMR) AF: 0.00 AC: 0 AN: 13914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3314

East Asian (EAS) AF: 0.00 AC: 0 AN: 4856

South Asian (SAS) AF: 0.00 AC: 0 AN: 4426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64426

Other (OTH) AF: 0.000527 AC: 1 AN: 1896

Alfa AF: 0.00 Hom.: 3

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.058

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516499; hg19: chr1-237905570;