19-38502739-C-T

Variant names:

• chr19-38502739-C-T
• rs755502084
• NM_000540.3:c.7835+12C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The ENST00000359596.8(RYR1):​c.7835+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,367,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RYR1 ENST00000359596.8 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.93
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.7835+12C>T		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.7835+12C>T		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.7835+12C>T		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.7835+12C>T		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.7835+12C>T		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0000112 AC: 1 AN: 89350 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000217

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000334 AC: 7 AN: 209446 AF XY: 0.0000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000636

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 15 AN: 1278078 Hom.: 0 Cov.: 36 AF XY: 0.00000945 AC XY: 6 AN XY: 634952

African (AFR) AF: 0.00 AC: 0 AN: 30486

American (AMR) AF: 0.000124 AC: 5 AN: 40372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20886

East Asian (EAS) AF: 0.0000339 AC: 1 AN: 29464

South Asian (SAS) AF: 0.0000502 AC: 4 AN: 79742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4910

European-Non Finnish (NFE) AF: 0.00000505 AC: 5 AN: 990182

Other (OTH) AF: 0.00 AC: 0 AN: 50938

GnomAD4 genome AF: 0.0000112 AC: 1 AN: 89350 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 41266

African (AFR) AF: 0.00 AC: 0 AN: 22752

American (AMR) AF: 0.00 AC: 0 AN: 6926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2564

East Asian (EAS) AF: 0.00 AC: 0 AN: 2672

South Asian (SAS) AF: 0.00 AC: 0 AN: 2426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 134

European-Non Finnish (NFE) AF: 0.0000217 AC: 1 AN: 46152

Other (OTH) AF: 0.00 AC: 0 AN: 1150

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.36
DANN	Benign	0.55
PhyloP100		-1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755502084; hg19: chr19-38993379;