rs73933018

Variant names:

• chr19-38546537-A-G
• rs73933018
• NM_000540.3:c.12094+11A>G

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.12094+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,609,702 control chromosomes in the GnomAD database, including 438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (229 hom., cov: 29)
  • Exomes 𝑓: 0.0033 (209 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.06
• Publications: 3 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), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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=-0.84).
• BP6: Variant 19-38546537-A-G is Benign according to our data. Variant chr19-38546537-A-G is described in ClinVar as Benign. ClinVar VariationId is 159832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.12094+11A>G		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.12079+11A>G		intron	N/A	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.12094+11A>G		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.12079+11A>G		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*2804+11A>G		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4548 AN: 151294 Hom.: 227 Cov.: 29

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00997

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000628

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.0222

GnomAD2 exomes AF: 0.00850 AC: 2136 AN: 251424 AF XY: 0.00603

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00332 AC: 4843 AN: 1458290 Hom.: 209 Cov.: 30 AF XY: 0.00291 AC XY: 2109 AN XY: 725730

African (AFR) AF: 0.114 AC: 3803 AN: 33392

American (AMR) AF: 0.00687 AC: 307 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.000210 AC: 233 AN: 1108842

Other (OTH) AF: 0.00722 AC: 435 AN: 60246

GnomAD4 genome AF: 0.0302 AC: 4569 AN: 151412 Hom.: 229 Cov.: 29 AF XY: 0.0295 AC XY: 2184 AN XY: 73942

African (AFR) AF: 0.106 AC: 4345 AN: 41178

American (AMR) AF: 0.00995 AC: 151 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5046

South Asian (SAS) AF: 0.000628 AC: 3 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67922

Other (OTH) AF: 0.0219 AC: 46 AN: 2096

Alfa AF: 0.0310 Hom.: 108

Bravo AF: 0.0349

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Malignant hyperthermia, susceptibility to, 1 (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	-0.84
CADD	Benign	0.27
DANN	Benign	0.63
PhyloP100		-1.1
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: rs73933018; hg19: chr19-39037177;