rs77592501

Variant names:

• chr19-38527637-C-T
• rs77592501
• NM_000540.3:c.10687-10C>T

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.10687-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0613 in 1,613,786 control chromosomes in the GnomAD database, including 4,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (382 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4431 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Scores: Splicing: ADA: 0.00006909
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.227
• Publications: 10 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-38527637-C-T is Benign according to our data. Variant chr19-38527637-C-T is described in ClinVar as Benign. ClinVar VariationId is 93241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 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.10687-10C>T		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10672-10C>T		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.10687-10C>T		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.10672-10C>T		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*1415-10C>T		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 8038 AN: 152182 Hom.: 382 Cov.: 32

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0599

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.0569

GnomAD2 exomes AF: 0.0791 AC: 19766 AN: 250028 AF XY: 0.0854

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.0632

Gnomad ASJ exome AF: 0.0668

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.0298

Gnomad NFE exome AF: 0.0516

Gnomad OTH exome AF: 0.0735

GnomAD4 exome AF: 0.0622 AC: 90853 AN: 1461486 Hom.: 4431 Cov.: 33 AF XY: 0.0667 AC XY: 48494 AN XY: 727046

African (AFR) AF: 0.0252 AC: 845 AN: 33476

American (AMR) AF: 0.0629 AC: 2809 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 1698 AN: 26120

East Asian (EAS) AF: 0.151 AC: 5991 AN: 39662

South Asian (SAS) AF: 0.213 AC: 18373 AN: 86154

European-Finnish (FIN) AF: 0.0317 AC: 1690 AN: 53334

Middle Eastern (MID) AF: 0.0940 AC: 542 AN: 5766

European-Non Finnish (NFE) AF: 0.0493 AC: 54842 AN: 1111928

Other (OTH) AF: 0.0673 AC: 4063 AN: 60384

GnomAD4 genome AF: 0.0528 AC: 8040 AN: 152300 Hom.: 382 Cov.: 32 AF XY: 0.0553 AC XY: 4120 AN XY: 74466

African (AFR) AF: 0.0244 AC: 1016 AN: 41584

American (AMR) AF: 0.0596 AC: 912 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3472

East Asian (EAS) AF: 0.174 AC: 899 AN: 5170

South Asian (SAS) AF: 0.227 AC: 1092 AN: 4816

European-Finnish (FIN) AF: 0.0267 AC: 284 AN: 10620

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0502 AC: 3417 AN: 68022

Other (OTH) AF: 0.0629 AC: 133 AN: 2114

Alfa AF: 0.0463 Hom.: 80

Bravo AF: 0.0498

Asia WGS AF: 0.227 AC: 787 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	-	2	not provided (2)
-	-	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	-0.81
CADD	Benign	8.6
DANN	Benign	0.74
PhyloP100		0.23
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.0060
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: rs77592501; hg19: chr19-39018277; COSMIC: COSV62092662; COSMIC: COSV62092662;