rs10925391

Variant names:

• chr1-237377315-A-C
• rs10925391
• NM_001035.3:c.464-8A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-237377315-A-C
• chr1-237377315-A-T
• chr1-237377315-A-G

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.464-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,595,424 control chromosomes in the GnomAD database, including 59,200 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9495 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49705 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002350
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -2.49
• Publications: 14 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=-0.89).
• BP6: Variant 1-237377315-A-C is Benign according to our data. Variant chr1-237377315-A-C is described in ClinVar as Benign. ClinVar VariationId is 43790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 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.464-8A>C		splice_region 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.464-8A>C		splice_region intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.464-8A>C		splice_region intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.464-8A>C		splice_region intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50500 AN: 151912 Hom.: 9467 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.316

GnomAD2 exomes AF: 0.290 AC: 69503 AN: 239434 AF XY: 0.279

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.435

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.253 AC: 365205 AN: 1443394 Hom.: 49705 Cov.: 28 AF XY: 0.251 AC XY: 179856 AN XY: 717104

African (AFR) AF: 0.509 AC: 16709 AN: 32830

American (AMR) AF: 0.344 AC: 14626 AN: 42506

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4606 AN: 25534

East Asian (EAS) AF: 0.479 AC: 18864 AN: 39374

South Asian (SAS) AF: 0.210 AC: 17552 AN: 83398

European-Finnish (FIN) AF: 0.357 AC: 18954 AN: 53042

Middle Eastern (MID) AF: 0.223 AC: 1262 AN: 5648

European-Non Finnish (NFE) AF: 0.234 AC: 257250 AN: 1101456

Other (OTH) AF: 0.258 AC: 15382 AN: 59606

GnomAD4 genome AF: 0.333 AC: 50567 AN: 152030 Hom.: 9495 Cov.: 32 AF XY: 0.336 AC XY: 24998 AN XY: 74298

African (AFR) AF: 0.501 AC: 20758 AN: 41442

American (AMR) AF: 0.323 AC: 4921 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 627 AN: 3470

East Asian (EAS) AF: 0.442 AC: 2281 AN: 5164

South Asian (SAS) AF: 0.216 AC: 1045 AN: 4828

European-Finnish (FIN) AF: 0.371 AC: 3925 AN: 10576

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16098 AN: 67980

Other (OTH) AF: 0.311 AC: 657 AN: 2110

Alfa AF: 0.265 Hom.: 17859

Bravo AF: 0.341

Asia WGS AF: 0.325 AC: 1128 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Catecholaminergic polymorphic ventricular tachycardia 1 (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 2 (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.53
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0020
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: rs10925391; hg19: chr1-237540615; COSMIC: COSV63672220;