1-237610751-C-T

Variant names:

• chr1-237610751-C-T
• rs7546045
• NM_001035.3:c.4684-11C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.4684-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,582,360 control chromosomes in the GnomAD database, including 1,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (710 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (681 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Scores: Splicing: ADA: 0.00002065
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.58
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-237610751-C-T is Benign according to our data. Variant chr1-237610751-C-T is described in ClinVar as Benign. ClinVar VariationId is 43791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

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.4684-11C>T		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.4684-11C>T		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.4684-11C>T		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.4684-11C>T		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8093 AN: 151978 Hom.: 706 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00888

Gnomad SAS AF: 0.0202

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0159 AC: 3390 AN: 213648 AF XY: 0.0133

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.00779

Gnomad ASJ exome AF: 0.000217

Gnomad EAS exome AF: 0.00673

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000644

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00682 AC: 9760 AN: 1430266 Hom.: 681 Cov.: 30 AF XY: 0.00649 AC XY: 4597 AN XY: 708220

African (AFR) AF: 0.198 AC: 6487 AN: 32830

American (AMR) AF: 0.00847 AC: 343 AN: 40474

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 3 AN: 25492

East Asian (EAS) AF: 0.00338 AC: 130 AN: 38480

South Asian (SAS) AF: 0.0177 AC: 1458 AN: 82504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52026

Middle Eastern (MID) AF: 0.0130 AC: 57 AN: 4374

European-Non Finnish (NFE) AF: 0.000380 AC: 416 AN: 1094880

Other (OTH) AF: 0.0146 AC: 866 AN: 59206

GnomAD4 genome AF: 0.0533 AC: 8110 AN: 152094 Hom.: 710 Cov.: 32 AF XY: 0.0517 AC XY: 3847 AN XY: 74356

African (AFR) AF: 0.183 AC: 7602 AN: 41442

American (AMR) AF: 0.0161 AC: 245 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00871 AC: 45 AN: 5168

South Asian (SAS) AF: 0.0194 AC: 93 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68022

Other (OTH) AF: 0.0355 AC: 75 AN: 2110

Alfa AF: 0.0534 Hom.: 453

Bravo AF: 0.0599

Asia WGS AF: 0.0330 AC: 116 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.55
DANN	Benign	0.50
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs7546045; hg19: chr1-237774051;