rs77310009

Variant names:

• chr19-38499974-C-T
• rs77310009
• NM_000540.3:c.7281C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.7281C>T​(p.Ala2427Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,614,144 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (32 hom., cov: 31)
  • Exomes 𝑓: 0.0050 (198 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -3.77
• Publications: 8 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), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-38499974-C-T is Benign according to our data. Variant chr19-38499974-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0618 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.7281C>T	p.Ala2427Ala	synonymous	Exon 45 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.7281C>T	p.Ala2427Ala	synonymous	Exon 45 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.7281C>T	p.Ala2427Ala	synonymous	Exon 45 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.7281C>T	p.Ala2427Ala	synonymous	Exon 45 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.7281C>T		non_coding_transcript_exon	Exon 45 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1270 AN: 152166 Hom.: 32 Cov.: 31

Gnomad AFR AF: 0.00429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0136 AC: 3414 AN: 251370 AF XY: 0.0121

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0596

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00501 AC: 7319 AN: 1461860 Hom.: 198 Cov.: 36 AF XY: 0.00527 AC XY: 3829 AN XY: 727232

African (AFR) AF: 0.00388 AC: 130 AN: 33480

American (AMR) AF: 0.0411 AC: 1838 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26136

East Asian (EAS) AF: 0.0728 AC: 2890 AN: 39700

South Asian (SAS) AF: 0.0201 AC: 1735 AN: 86248

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53412

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000177 AC: 197 AN: 1112004

Other (OTH) AF: 0.00748 AC: 452 AN: 60392

GnomAD4 genome AF: 0.00834 AC: 1270 AN: 152284 Hom.: 32 Cov.: 31 AF XY: 0.00984 AC XY: 733 AN XY: 74456

African (AFR) AF: 0.00428 AC: 178 AN: 41574

American (AMR) AF: 0.0372 AC: 569 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.0676 AC: 349 AN: 5160

South Asian (SAS) AF: 0.0253 AC: 122 AN: 4820

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68010

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00347 Hom.: 5

Bravo AF: 0.0109

Asia WGS AF: 0.0530 AC: 185 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (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	-0.68
CADD	Benign	1.7
DANN	Benign	0.57
PhyloP100		-3.8
Mutation Taster		=89/11	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: rs77310009; hg19: chr19-38990614; COSMIC: COSV62088367;