rs45613041

Variant names:

• chr19-38543411-T-A
• rs45613041
• NM_000540.3:c.11754T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38543411-T-A
• chr19-38543411-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.11754T>A​(p.Thr3918Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,614,218 control chromosomes in the GnomAD database, including 839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3918T) has been classified as Likely benign. The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.023 (95 hom., cov: 32)
  • Exomes 𝑓: 0.023 (744 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -4.67
• Publications: 10 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

Specifications for RYR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-38543411-T-A is Benign according to our data. Variant chr19-38543411-T-A is described in ClinVar as Benign. ClinVar VariationId is 133019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0692 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.11754T>A	p.Thr3918Thr	synonymous	Exon 85 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.11739T>A	p.Thr3913Thr	synonymous	Exon 84 of 105	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.11754T>A	p.Thr3918Thr	synonymous	Exon 85 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.11739T>A	p.Thr3913Thr	synonymous	Exon 84 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*2464T>A		non_coding_transcript_exon	Exon 82 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3468 AN: 152220 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.00796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0725

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0599

Gnomad SAS AF: 0.0327

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0349 AC: 8785 AN: 251492 AF XY: 0.0322

Gnomad AFR exome AF: 0.00744

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0477

Gnomad FIN exome AF: 0.0450

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0230 AC: 33650 AN: 1461880 Hom.: 744 Cov.: 32 AF XY: 0.0228 AC XY: 16552 AN XY: 727242

African (AFR) AF: 0.00645 AC: 216 AN: 33480

American (AMR) AF: 0.109 AC: 4873 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26136

East Asian (EAS) AF: 0.0681 AC: 2704 AN: 39698

South Asian (SAS) AF: 0.0293 AC: 2531 AN: 86258

European-Finnish (FIN) AF: 0.0442 AC: 2363 AN: 53420

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.0173 AC: 19254 AN: 1112000

Other (OTH) AF: 0.0264 AC: 1596 AN: 60396

GnomAD4 genome AF: 0.0228 AC: 3471 AN: 152338 Hom.: 95 Cov.: 32 AF XY: 0.0255 AC XY: 1899 AN XY: 74484

African (AFR) AF: 0.00791 AC: 329 AN: 41586

American (AMR) AF: 0.0727 AC: 1113 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.0598 AC: 310 AN: 5180

South Asian (SAS) AF: 0.0327 AC: 158 AN: 4830

European-Finnish (FIN) AF: 0.0444 AC: 471 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0152 AC: 1033 AN: 68038

Other (OTH) AF: 0.0236 AC: 50 AN: 2116

Alfa AF: 0.00836 Hom.: 5

Bravo AF: 0.0240

Asia WGS AF: 0.0590 AC: 205 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0142

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	-	2	not provided (3)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (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	-0.64
CADD	Benign	0.17
DANN	Benign	0.61
PhyloP100		-4.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45613041; hg19: chr19-39034051; COSMIC: COSV62089248; COSMIC: COSV62089248;