rs5828009

Variant names:

• chr19-38507857-G-GC
• rs5828009
• NM_000540.3:c.8932+34dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.8932+34dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.33 (8550 hom., cov: 0)
  • Exomes 𝑓: 0.27 (49339 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.483
• Publications: 7 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: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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: Genomics England PanelApp, G2P
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-38507857-G-GC is Benign according to our data. Variant chr19-38507857-G-GC is described in ClinVar as Benign. ClinVar VariationId is 256576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 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.8932+34dupC		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8932+34dupC		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.8932+30_8932+31insC		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.8932+30_8932+31insC		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.8932+30_8932+31insC		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49168 AN: 151454 Hom.: 8514 Cov.: 0

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.333

GnomAD2 exomes AF: 0.322 AC: 80321 AN: 249778 AF XY: 0.322

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.270 AC: 329869 AN: 1223892 Hom.: 49339 Cov.: 17 AF XY: 0.276 AC XY: 171019 AN XY: 620590

African (AFR) AF: 0.425 AC: 12074 AN: 28392

American (AMR) AF: 0.387 AC: 17119 AN: 44248

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6125 AN: 24650

East Asian (EAS) AF: 0.336 AC: 12880 AN: 38384

South Asian (SAS) AF: 0.444 AC: 35944 AN: 80980

European-Finnish (FIN) AF: 0.292 AC: 15477 AN: 52996

Middle Eastern (MID) AF: 0.328 AC: 1716 AN: 5230

European-Non Finnish (NFE) AF: 0.238 AC: 213433 AN: 896568

Other (OTH) AF: 0.288 AC: 15101 AN: 52444

GnomAD4 genome AF: 0.325 AC: 49265 AN: 151572 Hom.: 8550 Cov.: 0 AF XY: 0.332 AC XY: 24565 AN XY: 74008

African (AFR) AF: 0.429 AC: 17680 AN: 41236

American (AMR) AF: 0.355 AC: 5417 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 889 AN: 3468

East Asian (EAS) AF: 0.360 AC: 1846 AN: 5126

South Asian (SAS) AF: 0.460 AC: 2208 AN: 4800

European-Finnish (FIN) AF: 0.286 AC: 3005 AN: 10490

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17181 AN: 67900

Other (OTH) AF: 0.338 AC: 710 AN: 2102

Alfa AF: 0.275 Hom.: 1092

Bravo AF: 0.331

Asia WGS AF: 0.487 AC: 1692 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	King Denborough syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5828009;

hg19: chr19-38998497;