rs2915958

Variant names:

• chr19-38506819-G-C
• rs2915958
• NM_000540.3:c.8693-10G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-38506819-G-C
• chr19-38506819-G-A
• chr19-38506819-G-T

Variant summary

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

The NM_000540.3(RYR1):​c.8693-10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,554 control chromosomes in the GnomAD database, including 67,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8640 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58930 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Scores: Splicing: ADA: 0.009549
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: -0.424
• Publications: 14 publications found

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-38506819-G-C is Benign according to our data. Variant chr19-38506819-G-C is described in ClinVar as Benign. ClinVar VariationId is 93302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. 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
	RYR1	NM_000540.3	MANE Select	c.8693-10G>C		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8693-10G>C		intron	N/A	NP_001036188.1	P21817-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.8693-10G>C		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.8693-10G>C		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.8693-10G>C		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49482 AN: 151850 Hom.: 8604 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.321 AC: 80464 AN: 250388 AF XY: 0.321

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.276 AC: 403140 AN: 1461584 Hom.: 58930 Cov.: 44 AF XY: 0.280 AC XY: 203825 AN XY: 727098

African (AFR) AF: 0.433 AC: 14503 AN: 33474

American (AMR) AF: 0.388 AC: 17331 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6585 AN: 26136

East Asian (EAS) AF: 0.338 AC: 13416 AN: 39690

South Asian (SAS) AF: 0.447 AC: 38516 AN: 86230

European-Finnish (FIN) AF: 0.293 AC: 15599 AN: 53320

Middle Eastern (MID) AF: 0.337 AC: 1941 AN: 5760

European-Non Finnish (NFE) AF: 0.250 AC: 277499 AN: 1111908

Other (OTH) AF: 0.294 AC: 17750 AN: 60386

GnomAD4 genome AF: 0.326 AC: 49579 AN: 151970 Hom.: 8640 Cov.: 31 AF XY: 0.333 AC XY: 24772 AN XY: 74282

African (AFR) AF: 0.431 AC: 17869 AN: 41444

American (AMR) AF: 0.355 AC: 5419 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 891 AN: 3466

East Asian (EAS) AF: 0.363 AC: 1869 AN: 5150

South Asian (SAS) AF: 0.461 AC: 2222 AN: 4820

European-Finnish (FIN) AF: 0.289 AC: 3052 AN: 10556

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17220 AN: 67968

Other (OTH) AF: 0.337 AC: 710 AN: 2108

Alfa AF: 0.268 Hom.: 1116

Bravo AF: 0.333

Asia WGS AF: 0.488 AC: 1694 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Central core myopathy (2)
-	-	2	Congenital multicore myopathy with external ophthalmoplegia (2)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	1	1	not provided (3)
-	-	1	Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	King Denborough syndrome (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.4
DANN	Benign	0.69
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0095
dbscSNV1_RF	Benign	0.052
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: rs2915958; hg19: chr19-38997459; COSMIC: COSV62092647; COSMIC: COSV62092647;