NM_000540.3:c.5637C>T

Variant names:

• chr19-38489266-C-T
• rs143418190
• NM_000540.3:c.5637C>T

Variant summary

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

The NM_000540.3(RYR1):​c.5637C>T​(p.Asp1879Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,607,602 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 Conflicting classifications of pathogenicity (no stars). The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: -0.358
• Publications: 1 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

Specifications for RYR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-38489266-C-T is Benign according to our data. Variant chr19-38489266-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93276.
• BP7: Synonymous conserved (PhyloP=-0.358 with no splicing effect.

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.5637C>T	p.Asp1879Asp	synonymous	Exon 35 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.5637C>T	p.Asp1879Asp	synonymous	Exon 35 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.5637C>T	p.Asp1879Asp	synonymous	Exon 35 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.5637C>T	p.Asp1879Asp	synonymous	Exon 35 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.5637C>T		non_coding_transcript_exon	Exon 35 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0000866 AC: 13 AN: 150048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000739

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: 0.000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 25 AN: 247714 AF XY: 0.0000895

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 337 AN: 1457554 Hom.: 0 Cov.: 31 AF XY: 0.000201 AC XY: 146 AN XY: 725322

African (AFR) AF: 0.0000898 AC: 3 AN: 33398

American (AMR) AF: 0.000112 AC: 5 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000288 AC: 319 AN: 1108242

Other (OTH) AF: 0.000133 AC: 8 AN: 60264

GnomAD4 genome AF: 0.0000866 AC: 13 AN: 150048 Hom.: 0 Cov.: 32 AF XY: 0.0000684 AC XY: 5 AN XY: 73100

African (AFR) AF: 0.0000739 AC: 3 AN: 40592

American (AMR) AF: 0.00 AC: 0 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67586

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000147

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	RYR1-related disorder (2)
-	1	-	Central core myopathy (1)
-	1	-	Congenital multicore myopathy with external ophthalmoplegia (1)
-	1	-	Malignant hyperthermia, susceptibility to, 1 (1)
-	1	-	Neuromuscular disease, congenital, with uniform type 1 fiber (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.9
DANN	Benign	0.58
PhyloP100		-0.36
Mutation Taster		=99/1	polymorphism

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: rs143418190; hg19: chr19-38979906;