rs12460768

Variant names:

• chr19-38453088-G-A
• rs12460768
• NM_000540.3:c.1440+74G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38453088-G-A
• chr19-38453088-G-C
• chr19-38453088-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.1440+74G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,491,336 control chromosomes in the GnomAD database, including 321,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30963 hom., cov: 28)
  • Exomes 𝑓: 0.65 (290612 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -2.86
• 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=-0.82).
• BP6: Variant 19-38453088-G-A is Benign according to our data. Variant chr19-38453088-G-A is described in ClinVar as Benign. ClinVar VariationId is 133064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.683 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.1440+74G>A		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.1440+74G>A		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.1440+74G>A		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.1440+74G>A		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.1440+74G>A		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.635 AC: 95857 AN: 150968 Hom.: 30953 Cov.: 28

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.654 AC: 876462 AN: 1340252 Hom.: 290612 AF XY: 0.649 AC XY: 432720 AN XY: 667262

African (AFR) AF: 0.550 AC: 17090 AN: 31090

American (AMR) AF: 0.697 AC: 27306 AN: 39178

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 17119 AN: 24706

East Asian (EAS) AF: 0.659 AC: 24872 AN: 37730

South Asian (SAS) AF: 0.458 AC: 36866 AN: 80568

European-Finnish (FIN) AF: 0.691 AC: 33286 AN: 48170

Middle Eastern (MID) AF: 0.695 AC: 3243 AN: 4668

European-Non Finnish (NFE) AF: 0.668 AC: 679820 AN: 1018122

Other (OTH) AF: 0.658 AC: 36860 AN: 56020

GnomAD4 genome AF: 0.635 AC: 95907 AN: 151084 Hom.: 30963 Cov.: 28 AF XY: 0.631 AC XY: 46551 AN XY: 73746

African (AFR) AF: 0.552 AC: 22670 AN: 41104

American (AMR) AF: 0.694 AC: 10559 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2421 AN: 3464

East Asian (EAS) AF: 0.613 AC: 3120 AN: 5090

South Asian (SAS) AF: 0.444 AC: 2118 AN: 4766

European-Finnish (FIN) AF: 0.703 AC: 7349 AN: 10454

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.670 AC: 45375 AN: 67690

Other (OTH) AF: 0.648 AC: 1360 AN: 2098

Alfa AF: 0.538 Hom.: 1495

Bravo AF: 0.638

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.85
DANN	Benign	0.86
PhyloP100		-2.9
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: rs12460768; hg19: chr19-38943728; COSMIC: COSV62111492;