chr1-237742270-C-CTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 144 AD gene.

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.11092-13_11092-11dupTTT		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_11092-25insTTT		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.11092-26_11092-25insTTT		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*2127-26_*2127-25insTTT		intron	N/A	ENSP00000499659.2	A0A590UK06

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

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

African (AFR) AF: 0.00375 AC: 88 AN: 23478

American (AMR) AF: 0.000298 AC: 7 AN: 23486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19852

East Asian (EAS) AF: 0.0000659 AC: 2 AN: 30350

South Asian (SAS) AF: 0.000235 AC: 14 AN: 59460

European-Finnish (FIN) AF: 0.0000252 AC: 1 AN: 39666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3778

European-Non Finnish (NFE) AF: 0.000191 AC: 153 AN: 800218

Other (OTH) AF: 0.000382 AC: 17 AN: 44488

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00334 AC: 122 AN: 36532

American (AMR) AF: 0.000718 AC: 10 AN: 13924

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4840

South Asian (SAS) AF: 0.00 AC: 0 AN: 4402

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000140 AC: 9 AN: 64414

Other (OTH) AF: 0.00157 AC: 3 AN: 1908

Alfa AF: 0.00 Hom.: 3

ClinVar

ClinVar submissions

Significance: 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
Mutation Taster		=100/0	polymorphism

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;