NM_000540.3:c.11908-14A>G

Variant names:

• chr19-38543757-A-G
• rs2292799
• NM_000540.3:c.11908-14A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.11908-14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,611,892 control chromosomes in the GnomAD database, including 828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (89 hom., cov: 32)
  • Exomes 𝑓: 0.023 (739 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.144
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-38543757-A-G is Benign according to our data. Variant chr19-38543757-A-G is described in ClinVar as Benign. ClinVar VariationId is 133022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

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.11908-14A>G		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.11893-14A>G		intron	N/A	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.11908-14A>G		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.11893-14A>G		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*2618-14A>G		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3458 AN: 151828 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0720

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0610

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.0347 AC: 8650 AN: 249418 AF XY: 0.0319

Gnomad AFR exome AF: 0.00736

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0474

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0230 AC: 33543 AN: 1459946 Hom.: 739 Cov.: 36 AF XY: 0.0227 AC XY: 16506 AN XY: 726386

African (AFR) AF: 0.00636 AC: 213 AN: 33474

American (AMR) AF: 0.109 AC: 4859 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26134

East Asian (EAS) AF: 0.0681 AC: 2705 AN: 39700

South Asian (SAS) AF: 0.0293 AC: 2531 AN: 86254

European-Finnish (FIN) AF: 0.0441 AC: 2276 AN: 51616

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5766

European-Non Finnish (NFE) AF: 0.0173 AC: 19256 AN: 1111950

Other (OTH) AF: 0.0264 AC: 1591 AN: 60364

GnomAD4 genome AF: 0.0228 AC: 3461 AN: 151946 Hom.: 89 Cov.: 32 AF XY: 0.0255 AC XY: 1893 AN XY: 74256

African (AFR) AF: 0.00784 AC: 325 AN: 41458

American (AMR) AF: 0.0723 AC: 1103 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3460

East Asian (EAS) AF: 0.0609 AC: 314 AN: 5156

South Asian (SAS) AF: 0.0334 AC: 160 AN: 4794

European-Finnish (FIN) AF: 0.0444 AC: 470 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0152 AC: 1032 AN: 67922

Other (OTH) AF: 0.0237 AC: 50 AN: 2106

Alfa AF: 0.0224 Hom.: 36

Bravo AF: 0.0240

Asia WGS AF: 0.0590 AC: 205 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	-	2	not provided (3)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.97
DANN	Benign	0.54
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs2292799; hg19: chr19-39034397;