rs908644

Variant names:

• chr19-38528088-C-G
• rs908644
• NM_000540.3:c.10825-218C>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.10825-218C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 632,186 control chromosomes in the GnomAD database, including 11,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.22 (4233 hom., cov: 31)
  • Exomes 𝑓: 0.17 (7649 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.204
• 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: 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

ENSG00000269445 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-38528088-C-G is Benign according to our data. Variant chr19-38528088-C-G is described in ClinVar as Benign. ClinVar VariationId is 133000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.356 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.10825-218C>G		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10810-218C>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.10825-218C>G		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.10810-218C>G		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*1553-218C>G		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32756 AN: 151604 Hom.: 4215 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.185 AC: 13159 AN: 71204 AF XY: 0.183

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.164

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.168 AC: 80532 AN: 480464 Hom.: 7649 Cov.: 5 AF XY: 0.172 AC XY: 43965 AN XY: 255524

African (AFR) AF: 0.372 AC: 4987 AN: 13416

American (AMR) AF: 0.148 AC: 3498 AN: 23700

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 2674 AN: 14836

East Asian (EAS) AF: 0.148 AC: 4667 AN: 31428

South Asian (SAS) AF: 0.269 AC: 13237 AN: 49258

European-Finnish (FIN) AF: 0.164 AC: 4895 AN: 29928

Middle Eastern (MID) AF: 0.208 AC: 439 AN: 2114

European-Non Finnish (NFE) AF: 0.143 AC: 41320 AN: 288614

Other (OTH) AF: 0.177 AC: 4815 AN: 27170

GnomAD4 genome AF: 0.216 AC: 32824 AN: 151722 Hom.: 4233 Cov.: 31 AF XY: 0.220 AC XY: 16302 AN XY: 74178

African (AFR) AF: 0.360 AC: 14892 AN: 41310

American (AMR) AF: 0.181 AC: 2764 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 618 AN: 3470

East Asian (EAS) AF: 0.175 AC: 902 AN: 5142

South Asian (SAS) AF: 0.284 AC: 1364 AN: 4806

European-Finnish (FIN) AF: 0.162 AC: 1705 AN: 10552

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9843 AN: 67888

Other (OTH) AF: 0.215 AC: 452 AN: 2102

Alfa AF: 0.178 Hom.: 388

Bravo AF: 0.220

Asia WGS AF: 0.286 AC: 995 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.7
DANN	Benign	0.60
PhyloP100		-0.20
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: rs908644; hg19: chr19-39018728; COSMIC: COSV107443157; COSMIC: COSV107443157;