rs2229145

Variant names:

• chr19-38519383-C-T
• rs2229145
• NM_000540.3:c.10188C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38519383-C-T
• chr19-38519383-C-A
• chr19-38519383-C-G

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.10188C>T​(p.Asp3396Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,605,854 control chromosomes in the GnomAD database, including 1,729 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 0.042 (199 hom., cov: 31)
  • Exomes 𝑓: 0.042 (1530 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:15 O:1
• Conservation: PhyloP100: -1.58
• Publications: 13 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=-0.5).
• BP6: Variant 19-38519383-C-T is Benign according to our data. Variant chr19-38519383-C-T is described in ClinVar as Benign. ClinVar VariationId is 93239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.58 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0627 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.10188C>T	p.Asp3396Asp	synonymous	Exon 67 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10188C>T	p.Asp3396Asp	synonymous	Exon 67 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.10188C>T	p.Asp3396Asp	synonymous	Exon 67 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.10188C>T	p.Asp3396Asp	synonymous	Exon 67 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*931C>T		non_coding_transcript_exon	Exon 66 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6330 AN: 152176 Hom.: 199 Cov.: 31

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0487

GnomAD2 exomes AF: 0.0444 AC: 10363 AN: 233166 AF XY: 0.0446

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0744

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0498

Gnomad OTH exome AF: 0.0553

GnomAD4 exome AF: 0.0421 AC: 61154 AN: 1453560 Hom.: 1530 Cov.: 32 AF XY: 0.0422 AC XY: 30469 AN XY: 722606

African (AFR) AF: 0.0127 AC: 422 AN: 33228

American (AMR) AF: 0.0281 AC: 1223 AN: 43460

Ashkenazi Jewish (ASJ) AF: 0.0772 AC: 2002 AN: 25928

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39150

South Asian (SAS) AF: 0.0237 AC: 2023 AN: 85298

European-Finnish (FIN) AF: 0.115 AC: 6072 AN: 52846

Middle Eastern (MID) AF: 0.0686 AC: 350 AN: 5102

European-Non Finnish (NFE) AF: 0.0419 AC: 46416 AN: 1108534

Other (OTH) AF: 0.0440 AC: 2640 AN: 60014

GnomAD4 genome AF: 0.0416 AC: 6329 AN: 152294 Hom.: 199 Cov.: 31 AF XY: 0.0450 AC XY: 3348 AN XY: 74466

African (AFR) AF: 0.0130 AC: 540 AN: 41572

American (AMR) AF: 0.0402 AC: 615 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 276 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0244 AC: 118 AN: 4832

European-Finnish (FIN) AF: 0.118 AC: 1254 AN: 10604

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0498 AC: 3387 AN: 68016

Other (OTH) AF: 0.0477 AC: 101 AN: 2116

Alfa AF: 0.0434 Hom.: 332

Bravo AF: 0.0355

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	1	2	not provided (4)
-	-	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	-0.50
CADD	Benign	0.25
DANN	Benign	0.70
PhyloP100		-1.6
Mutation Taster		=99/1	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: rs2229145; hg19: chr19-39010023; COSMIC: COSV62097516; COSMIC: COSV62097516;