NM_000540.3:c.8589T>C

Variant names:

• chr19-38506350-T-C
• rs2229146
• NM_000540.3:c.8589T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The c.8589T>C (p.Ser2863=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 40732/91032, 9442 homozygotes) of the c.8589T>C variant in RYR1 is 0.4430 for South Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA024932/MONDO:0100150/179

• Frequency:
  • Genomes: 𝑓 0.33 (8774 hom., cov: 30)
  • Exomes 𝑓: 0.28 (61178 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:19 O:1
• Conservation: PhyloP100: -2.77
• Publications: 24 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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.8589T>C	p.Ser2863Ser	synonymous	Exon 55 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8589T>C	p.Ser2863Ser	synonymous	Exon 55 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.8589T>C	p.Ser2863Ser	synonymous	Exon 55 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.8589T>C	p.Ser2863Ser	synonymous	Exon 55 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.8589T>C		non_coding_transcript_exon	Exon 55 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49936 AN: 151576 Hom.: 8738 Cov.: 30

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.334

GnomAD2 exomes AF: 0.325 AC: 81757 AN: 251438 AF XY: 0.325

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.282 AC: 411856 AN: 1461712 Hom.: 61178 Cov.: 47 AF XY: 0.286 AC XY: 208090 AN XY: 727186

African (AFR) AF: 0.434 AC: 14534 AN: 33474

American (AMR) AF: 0.389 AC: 17389 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6652 AN: 26136

East Asian (EAS) AF: 0.338 AC: 13422 AN: 39700

South Asian (SAS) AF: 0.447 AC: 38533 AN: 86250

European-Finnish (FIN) AF: 0.301 AC: 16102 AN: 53420

Middle Eastern (MID) AF: 0.338 AC: 1945 AN: 5762

European-Non Finnish (NFE) AF: 0.257 AC: 285224 AN: 1111866

Other (OTH) AF: 0.299 AC: 18055 AN: 60388

GnomAD4 genome AF: 0.330 AC: 50033 AN: 151694 Hom.: 8774 Cov.: 30 AF XY: 0.337 AC XY: 24961 AN XY: 74118

African (AFR) AF: 0.432 AC: 17858 AN: 41332

American (AMR) AF: 0.358 AC: 5457 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 903 AN: 3466

East Asian (EAS) AF: 0.360 AC: 1839 AN: 5112

South Asian (SAS) AF: 0.460 AC: 2199 AN: 4782

European-Finnish (FIN) AF: 0.299 AC: 3157 AN: 10564

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.259 AC: 17575 AN: 67874

Other (OTH) AF: 0.339 AC: 712 AN: 2102

Alfa AF: 0.286 Hom.: 19284

Bravo AF: 0.336

Asia WGS AF: 0.487 AC: 1692 AN: 3478

EpiCase AF: 0.268

EpiControl AF: 0.270

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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)
-	-	1	RYR1-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.6
DANN	Benign	0.54
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2229146; hg19: chr19-38996990; COSMIC: COSV62092503;