rs147213895

Variant names:

• chr19-38499241-A-G
• rs147213895
• NM_000540.3:c.7025A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS2 BS1

This summary comes from the ClinGen Evidence Repository: The c.7025A>G (NM_000540.3(RYR1):c.7025A>G (p.Asn2342Ser)) variant in RYR1 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 2342 (p.Asn2342Ser). The highest MAF in gnomAD v4.1.0 is 0.001818 (2145/1180004 alleles) in the European (non-Finnish) population, which is greater than the ClinGen Congenital Myopathies VCEP threshold (≥0.000697) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 3 homozygous individuals with no features of RYR1-related myopathy, a condition with full penetrance at an early age (BS2). The computational predictor REVEL gives a score of 0.639, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. The variant is near the end of the exon, but the highest SpliceAI score is 0.04 for donor gain, and the other scores are 0.00, indicating no significant impact to splicing is predicted (no codes met). This variant was found in six probands from five families (two compound heterozygous and three heterozygous cases). However, none of these probands were scored due to the high population allele frequency, and, in specific cases, a potentially causative RYR1 variant on the same allele, a causative variant in another gene, or lack of phenotypic detail/specificity (no codes met; Synnovis Internal Data; PMIDs: 23826317, 31903994, 38982518). In summary, this variant meets the criteria to be classified as benign for RYR1-related myopathy (undetermined mode of inheritance) based on the ACMG/AMP criteria applied, as specified by theClinGen Congenital Myopathy VCEP: (BS1, BS2; ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 02/10/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA024665/MONDO:0100150/150

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: RYR1 NM_000540.3 missense, splice_region
• Scores: Splicing: ADA: 0.007624
• Clinical Significance: Benign/Likely benign reviewed by expert panel U:9 B:14 O:2
• Conservation: PhyloP100: 9.32
• Publications: 27 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 -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.7025A>G	p.Asn2342Ser	missense splice_region	Exon 43 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.7025A>G	p.Asn2342Ser	missense splice_region	Exon 43 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.7025A>G	p.Asn2342Ser	missense splice_region	Exon 43 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.7025A>G	p.Asn2342Ser	missense splice_region	Exon 43 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.7025A>G		splice_region non_coding_transcript_exon	Exon 43 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00104 AC: 262 AN: 251376 AF XY: 0.00124

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00156 AC: 2278 AN: 1461864 Hom.: 3 Cov.: 32 AF XY: 0.00157 AC XY: 1141 AN XY: 727238

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86258

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00182 AC: 2024 AN: 1112000

Other (OTH) AF: 0.00103 AC: 62 AN: 60396

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74440

African (AFR) AF: 0.000409 AC: 17 AN: 41548

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68004

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00169 Hom.: 2

Bravo AF: 0.000960

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00107 AC: 130

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	5	Malignant hyperthermia, susceptibility to, 1 (8)
-	2	3	not provided (6)
-	1	1	not specified (2)
-	1	1	RYR1-related disorder (2)
-	1	-	Centronuclear myopathy (1)
-	-	1	Hereditary skeletal muscle disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	Malignant hyperthermia of anesthesia (1)
-	-	1	RYR1-related myopathy (1)
-	-	-	Congenital myopathy with fiber type disproportion;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.11	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.64
Sift	Benign	0.053	T
Polyphen		1.0	D
Vest4		0.68
MVP		0.98
MPC		0.25
ClinPred		0.11	T
GERP RS		3.7
Varity_R		0.28
gMVP		0.90
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0076
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.040		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: rs147213895; hg19: chr19-38989881;