rs2229144

Variant names:

• chr19-38504270-G-A
• rs2229144
• NM_000540.3:c.7977G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38504270-G-A
• chr19-38504270-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.7977G>A​(p.Thr2659Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,613,528 control chromosomes in the GnomAD database, including 68,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9214 hom., cov: 31)
  • Exomes 𝑓: 0.28 (59100 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: -5.01
• Publications: 21 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-38504270-G-A is Benign according to our data. Variant chr19-38504270-G-A is described in ClinVar as Benign. ClinVar VariationId is 93296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.455 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.7977G>A	p.Thr2659Thr	synonymous	Exon 50 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.7977G>A	p.Thr2659Thr	synonymous	Exon 50 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.7977G>A	p.Thr2659Thr	synonymous	Exon 50 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.7977G>A	p.Thr2659Thr	synonymous	Exon 50 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.7977G>A		non_coding_transcript_exon	Exon 50 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50690 AN: 151704 Hom.: 9172 Cov.: 31

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.339

GnomAD2 exomes AF: 0.323 AC: 81058 AN: 250988 AF XY: 0.322

Gnomad AFR exome AF: 0.470

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.276 AC: 403687 AN: 1461706 Hom.: 59100 Cov.: 38 AF XY: 0.280 AC XY: 203818 AN XY: 727140

African (AFR) AF: 0.464 AC: 15516 AN: 33474

American (AMR) AF: 0.390 AC: 17443 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6844 AN: 26134

East Asian (EAS) AF: 0.338 AC: 13421 AN: 39698

South Asian (SAS) AF: 0.437 AC: 37724 AN: 86240

European-Finnish (FIN) AF: 0.293 AC: 15633 AN: 53406

Middle Eastern (MID) AF: 0.339 AC: 1956 AN: 5766

European-Non Finnish (NFE) AF: 0.249 AC: 277275 AN: 1111894

Other (OTH) AF: 0.296 AC: 17875 AN: 60392

GnomAD4 genome AF: 0.335 AC: 50791 AN: 151822 Hom.: 9214 Cov.: 31 AF XY: 0.341 AC XY: 25302 AN XY: 74180

African (AFR) AF: 0.460 AC: 19045 AN: 41358

American (AMR) AF: 0.358 AC: 5464 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3470

East Asian (EAS) AF: 0.362 AC: 1862 AN: 5150

South Asian (SAS) AF: 0.449 AC: 2162 AN: 4814

European-Finnish (FIN) AF: 0.289 AC: 3045 AN: 10528

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.254 AC: 17228 AN: 67952

Other (OTH) AF: 0.344 AC: 723 AN: 2100

Alfa AF: 0.286 Hom.: 6219

Bravo AF: 0.343

Asia WGS AF: 0.485 AC: 1683 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.265

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Central core myopathy (2)
-	-	2	Congenital multicore myopathy with external ophthalmoplegia (2)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	1	1	not provided (3)
-	-	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	-0.71
CADD	Benign	0.35
DANN	Benign	0.66
PhyloP100		-5.0
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs2229144; hg19: chr19-38994910; COSMIC: COSV62092617;