19-38433746-G-GC

Variant names:

• chr19-38433746-G-GC
• rs886054374
• NM_000540.3:c.-81dupC

Variant summary

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

The NM_000540.3(RYR1):​c.-81dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0031 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: 2.43
• 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), 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: Uncertain_significance. The variant received 0 ACMG points.

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.-81dupC		5_prime_UTR	Exon 1 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.-81dupC		5_prime_UTR	Exon 1 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.-81dupC		5_prime_UTR	Exon 1 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.-81dupC		5_prime_UTR	Exon 1 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.-81dupC		non_coding_transcript_exon	Exon 1 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0000207 AC: 3 AN: 145246 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000257

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: 0.000104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00308 AC: 1155 AN: 374914 Hom.: 2 Cov.: 0 AF XY: 0.00286 AC XY: 598 AN XY: 208814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00628 AC: 67 AN: 10668

American (AMR) AF: 0.0131 AC: 373 AN: 28532

Ashkenazi Jewish (ASJ) AF: 0.00660 AC: 83 AN: 12570

East Asian (EAS) AF: 0.000507 AC: 9 AN: 17758

South Asian (SAS) AF: 0.00325 AC: 195 AN: 59932

European-Finnish (FIN) AF: 0.00107 AC: 25 AN: 23316

Middle Eastern (MID) AF: 0.00935 AC: 13 AN: 1390

European-Non Finnish (NFE) AF: 0.00172 AC: 348 AN: 202688

Other (OTH) AF: 0.00233 AC: 42 AN: 18060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000207 AC: 3 AN: 145246 Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 1 AN XY: 70886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000257 AC: 1 AN: 38872

American (AMR) AF: 0.00 AC: 0 AN: 14658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 4702

South Asian (SAS) AF: 0.00 AC: 0 AN: 4406

European-Finnish (FIN) AF: 0.000104 AC: 1 AN: 9594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66412

Other (OTH) AF: 0.00 AC: 0 AN: 1988

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Central core myopathy (1)
-	1	-	Malignant hyperthermia of anesthesia (1)
-	1	-	Multiminicore myopathy (1)
-	1	-	Neuromuscular disease, congenital, with uniform type 1 fiber (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

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

Other links and lift over

dbSNP: rs886054374; hg19: chr19-38924386;