rs2288888

Variant names:

• chr19-38455542-G-A
• rs2288888
• NM_000540.3:c.1668G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38455542-G-A
• chr19-38455542-G-C

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.1668G>A​(p.Ser556Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,613,334 control chromosomes in the GnomAD database, including 347,615 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 0.64 (31370 hom., cov: 31)
  • Exomes 𝑓: 0.65 (316245 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22 O:1
• Conservation: PhyloP100: -4.99
• Publications: 31 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

Specifications for RYR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-38455542-G-A is Benign according to our data. Variant chr19-38455542-G-A is described in ClinVar as Benign. ClinVar VariationId is 93258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.687 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.1668G>A	p.Ser556Ser	synonymous	Exon 15 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.1668G>A	p.Ser556Ser	synonymous	Exon 15 of 105	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.1668G>A	p.Ser556Ser	synonymous	Exon 15 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.1668G>A	p.Ser556Ser	synonymous	Exon 15 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.1668G>A		non_coding_transcript_exon	Exon 15 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96765 AN: 151790 Hom.: 31361 Cov.: 31

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.656

GnomAD2 exomes AF: 0.642 AC: 161310 AN: 251256 AF XY: 0.636

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.695

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.618

Gnomad FIN exome AF: 0.705

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.677

GnomAD4 exome AF: 0.655 AC: 957134 AN: 1461426 Hom.: 316245 Cov.: 48 AF XY: 0.650 AC XY: 472495 AN XY: 727002

African (AFR) AF: 0.548 AC: 18349 AN: 33474

American (AMR) AF: 0.694 AC: 31052 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 18098 AN: 26132

East Asian (EAS) AF: 0.656 AC: 26048 AN: 39696

South Asian (SAS) AF: 0.463 AC: 39968 AN: 86250

European-Finnish (FIN) AF: 0.699 AC: 37315 AN: 53404

Middle Eastern (MID) AF: 0.694 AC: 4001 AN: 5768

European-Non Finnish (NFE) AF: 0.668 AC: 742659 AN: 1111620

Other (OTH) AF: 0.657 AC: 39644 AN: 60370

GnomAD4 genome AF: 0.637 AC: 96812 AN: 151908 Hom.: 31370 Cov.: 31 AF XY: 0.635 AC XY: 47112 AN XY: 74250

African (AFR) AF: 0.551 AC: 22804 AN: 41386

American (AMR) AF: 0.698 AC: 10664 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 2431 AN: 3466

East Asian (EAS) AF: 0.610 AC: 3142 AN: 5152

South Asian (SAS) AF: 0.449 AC: 2160 AN: 4812

European-Finnish (FIN) AF: 0.716 AC: 7577 AN: 10584

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.673 AC: 45723 AN: 67930

Other (OTH) AF: 0.650 AC: 1369 AN: 2106

Alfa AF: 0.660 Hom.: 68889

Bravo AF: 0.638

Asia WGS AF: 0.459 AC: 1599 AN: 3478

EpiCase AF: 0.678

EpiControl AF: 0.687

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (4)
-	-	2	Central core myopathy (2)
-	-	2	Congenital multicore myopathy with external ophthalmoplegia (2)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	-	1	Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	King Denborough syndrome (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	1.8
DANN	Benign	0.85
PhyloP100		-5.0
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: rs2288888; hg19: chr19-38946182; COSMIC: COSV62095035;