rs12563366

Variant names:

• chr1-237633550-A-G
• rs12563366
• NM_001035.3:c.6556-28A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-237633550-A-G
• chr1-237633550-A-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.6556-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 1,612,786 control chromosomes in the GnomAD database, including 8,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.11 (1251 hom., cov: 33)
  • Exomes 𝑓: 0.074 (7141 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.153
• Publications: 6 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: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-237633550-A-G is Benign according to our data. Variant chr1-237633550-A-G is described in ClinVar as Benign. ClinVar VariationId is 257213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.6556-28A>G		intron_variant	Intron 42 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.6556-28A>G		intron_variant	Intron 42 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.6556-28A>G		intron_variant	Intron 42 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.6556-28A>G		intron_variant	Intron 42 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16392 AN: 152106 Hom.: 1250 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0804

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.111 AC: 27680 AN: 248400 AF XY: 0.102

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.0835

Gnomad EAS exome AF: 0.323

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0587

Gnomad OTH exome AF: 0.0947

GnomAD4 exome AF: 0.0736 AC: 107520 AN: 1460562 Hom.: 7141 Cov.: 32 AF XY: 0.0723 AC XY: 52498 AN XY: 726510

African (AFR) AF: 0.161 AC: 5374 AN: 33412

American (AMR) AF: 0.206 AC: 9197 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.0811 AC: 2114 AN: 26078

East Asian (EAS) AF: 0.395 AC: 15653 AN: 39672

South Asian (SAS) AF: 0.0578 AC: 4976 AN: 86122

European-Finnish (FIN) AF: 0.103 AC: 5475 AN: 53358

Middle Eastern (MID) AF: 0.102 AC: 587 AN: 5764

European-Non Finnish (NFE) AF: 0.0531 AC: 58972 AN: 1111254

Other (OTH) AF: 0.0857 AC: 5172 AN: 60330

GnomAD4 genome AF: 0.108 AC: 16402 AN: 152224 Hom.: 1251 Cov.: 33 AF XY: 0.112 AC XY: 8312 AN XY: 74402

African (AFR) AF: 0.154 AC: 6413 AN: 41544

American (AMR) AF: 0.145 AC: 2222 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3470

East Asian (EAS) AF: 0.343 AC: 1770 AN: 5156

South Asian (SAS) AF: 0.0603 AC: 291 AN: 4822

European-Finnish (FIN) AF: 0.115 AC: 1219 AN: 10606

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0563 AC: 3830 AN: 68030

Other (OTH) AF: 0.118 AC: 248 AN: 2106

Alfa AF: 0.0757 Hom.: 380

Bravo AF: 0.118

Asia WGS AF: 0.163 AC: 565 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.0
DANN	Benign	0.47
PhyloP100		0.15
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12563366; hg19: chr1-237796850; COSMIC: COSV63672224;