rs200780880

Variant names:

• chr19-38467812-C-T
• rs200780880
• NM_000540.3:c.3381C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The ENST00000359596.8(RYR1):​c.3381C>T​(p.Arg1127Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: RYR1 ENST00000359596.8 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004137
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.467
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 19-38467812-C-T is Benign according to our data. Variant chr19-38467812-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256491.
• BP7: Synonymous conserved (PhyloP=-0.467 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359596.8. 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.3381C>T	p.Arg1127Arg	splice_region synonymous	Exon 25 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.3381C>T	p.Arg1127Arg	splice_region synonymous	Exon 25 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.3381C>T	p.Arg1127Arg	splice_region synonymous	Exon 25 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.3381C>T	p.Arg1127Arg	splice_region synonymous	Exon 25 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.3381C>T		splice_region non_coding_transcript_exon	Exon 25 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000260 AC: 65 AN: 249884 AF XY: 0.000266

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1461530 Hom.: 1 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 727070

African (AFR) AF: 0.000299 AC: 10 AN: 33472

American (AMR) AF: 0.000559 AC: 25 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5690

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1111952

Other (OTH) AF: 0.000414 AC: 25 AN: 60366

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74468

African (AFR) AF: 0.000577 AC: 24 AN: 41586

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000431

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	1	Central core myopathy (1)
-	-	1	Malignant hyperthermia of anesthesia (1)
-	-	1	Malignant hyperthermia, susceptibility to, 1 (1)
-	-	1	Multiminicore myopathy (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	not specified (1)
-	1	-	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.9
DANN	Benign	0.81
PhyloP100		-0.47
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.066
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: rs200780880; hg19: chr19-38958452; COSMIC: COSV62094480;