rs2960345

Variant names:

• chr19-38506574-T-G
• rs2960345
• NM_000540.3:c.8692+28T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38506574-T-G
• chr19-38506574-T-A
• chr19-38506574-T-C

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.8692+28T>G 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 1,610,966 control chromosomes in the GnomAD database, including 67,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8624 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58833 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -2.80
• Publications: 7 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=-0.87).
• BP6: Variant 19-38506574-T-G is Benign according to our data. Variant chr19-38506574-T-G is described in ClinVar as Benign. ClinVar VariationId is 133233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.443 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.8692+28T>G		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8692+28T>G		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.8692+28T>G		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.8692+28T>G		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.8692+28T>G		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49444 AN: 151864 Hom.: 8588 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.322 AC: 79487 AN: 246590 AF XY: 0.322

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.341

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.276 AC: 402549 AN: 1458984 Hom.: 58833 Cov.: 33 AF XY: 0.280 AC XY: 203542 AN XY: 725924

African (AFR) AF: 0.433 AC: 14488 AN: 33424

American (AMR) AF: 0.388 AC: 17274 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6580 AN: 26120

East Asian (EAS) AF: 0.338 AC: 13414 AN: 39664

South Asian (SAS) AF: 0.447 AC: 38492 AN: 86174

European-Finnish (FIN) AF: 0.292 AC: 15506 AN: 53082

Middle Eastern (MID) AF: 0.337 AC: 1937 AN: 5746

European-Non Finnish (NFE) AF: 0.250 AC: 277121 AN: 1109902

Other (OTH) AF: 0.294 AC: 17737 AN: 60300

GnomAD4 genome AF: 0.326 AC: 49541 AN: 151982 Hom.: 8624 Cov.: 31 AF XY: 0.333 AC XY: 24744 AN XY: 74296

African (AFR) AF: 0.431 AC: 17844 AN: 41414

American (AMR) AF: 0.355 AC: 5422 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 893 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1854 AN: 5154

South Asian (SAS) AF: 0.459 AC: 2208 AN: 4808

European-Finnish (FIN) AF: 0.289 AC: 3059 AN: 10582

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

European-Non Finnish (NFE) AF: 0.253 AC: 17222 AN: 67984

Other (OTH) AF: 0.337 AC: 710 AN: 2104

Alfa AF: 0.238 Hom.: 1494

Bravo AF: 0.333

Asia WGS AF: 0.487 AC: 1691 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	King Denborough syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.20
DANN	Benign	0.28
PhyloP100		-2.8
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: rs2960345; hg19: chr19-38997214; COSMIC: COSV62092516; COSMIC: COSV62092516;