rs10925485

Variant names:

• chr1-237659956-A-C
• rs10925485
• NM_001035.3:c.8209-29A>C

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.8209-29A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 1,484,206 control chromosomes in the GnomAD database, including 2,139 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 0.060 (331 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1808 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.925
• 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: Ambry Genetics, Laboratory for Molecular Medicine
• catecholaminergic polymorphic ventricular tachycardia

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 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=-0.69).
• BP6: Variant 1-237659956-A-C is Benign according to our data. Variant chr1-237659956-A-C is described in ClinVar as Benign. ClinVar VariationId is 257218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0883 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.8209-29A>C		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.8209-29A>C		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.8209-29A>C		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.8209-29A>C		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0597 AC: 9082 AN: 152128 Hom.: 329 Cov.: 32

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0482

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0522

Gnomad OTH AF: 0.0598

GnomAD2 exomes AF: 0.0452 AC: 8864 AN: 196322 AF XY: 0.0444

Gnomad AFR exome AF: 0.0884

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.0739

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.0535

Gnomad OTH exome AF: 0.0466

GnomAD4 exome AF: 0.0493 AC: 65686 AN: 1331962 Hom.: 1808 Cov.: 19 AF XY: 0.0481 AC XY: 32016 AN XY: 665620

African (AFR) AF: 0.0971 AC: 2814 AN: 28970

American (AMR) AF: 0.0330 AC: 1108 AN: 33532

Ashkenazi Jewish (ASJ) AF: 0.0715 AC: 1734 AN: 24238

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37318

South Asian (SAS) AF: 0.00684 AC: 507 AN: 74120

European-Finnish (FIN) AF: 0.0573 AC: 2991 AN: 52182

Middle Eastern (MID) AF: 0.0339 AC: 188 AN: 5538

European-Non Finnish (NFE) AF: 0.0526 AC: 53627 AN: 1020462

Other (OTH) AF: 0.0488 AC: 2716 AN: 55602

GnomAD4 genome AF: 0.0597 AC: 9096 AN: 152244 Hom.: 331 Cov.: 32 AF XY: 0.0584 AC XY: 4348 AN XY: 74444

African (AFR) AF: 0.0907 AC: 3769 AN: 41542

American (AMR) AF: 0.0481 AC: 736 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 266 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4830

European-Finnish (FIN) AF: 0.0535 AC: 568 AN: 10614

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0522 AC: 3552 AN: 68004

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0559 Hom.: 67

Bravo AF: 0.0605

Asia WGS AF: 0.00983 AC: 34 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.5
DANN	Benign	0.72
PhyloP100		0.93
BranchPoint Hunter		3.0
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: rs10925485; hg19: chr1-237823256; COSMIC: COSV107461893;