NM_000540.3:c.2943G>A

Variant names:

• chr19-38466163-G-A
• rs2228069
• NM_000540.3:c.2943G>A

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.2943G>A​(p.Thr981Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,612,930 control chromosomes in the GnomAD database, including 293,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T981T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.60 (27393 hom., cov: 32)
  • Exomes 𝑓: 0.60 (266182 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: -3.04
• Publications: 26 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=-0.7).
• BP6: Variant 19-38466163-G-A is Benign according to our data. Variant chr19-38466163-G-A is described in ClinVar as Benign. ClinVar VariationId is 93261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.656 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.2943G>A	p.Thr981Thr	synonymous	Exon 24 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.2943G>A	p.Thr981Thr	synonymous	Exon 24 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.2943G>A	p.Thr981Thr	synonymous	Exon 24 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.2943G>A	p.Thr981Thr	synonymous	Exon 24 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.2943G>A		non_coding_transcript_exon	Exon 24 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90855 AN: 151958 Hom.: 27381 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.707

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.616

GnomAD2 exomes AF: 0.594 AC: 146801 AN: 247338 AF XY: 0.587

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.684

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.545

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.601 AC: 878139 AN: 1460854 Hom.: 266182 Cov.: 68 AF XY: 0.597 AC XY: 433723 AN XY: 726798

African (AFR) AF: 0.564 AC: 18871 AN: 33474

American (AMR) AF: 0.680 AC: 30335 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 16789 AN: 26108

East Asian (EAS) AF: 0.591 AC: 23438 AN: 39678

South Asian (SAS) AF: 0.451 AC: 38911 AN: 86216

European-Finnish (FIN) AF: 0.581 AC: 30744 AN: 52938

Middle Eastern (MID) AF: 0.656 AC: 3784 AN: 5766

European-Non Finnish (NFE) AF: 0.610 AC: 678271 AN: 1111724

Other (OTH) AF: 0.613 AC: 36996 AN: 60344

GnomAD4 genome AF: 0.598 AC: 90902 AN: 152076 Hom.: 27393 Cov.: 32 AF XY: 0.593 AC XY: 44094 AN XY: 74320

African (AFR) AF: 0.564 AC: 23389 AN: 41476

American (AMR) AF: 0.667 AC: 10178 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2255 AN: 3470

East Asian (EAS) AF: 0.535 AC: 2761 AN: 5156

South Asian (SAS) AF: 0.437 AC: 2112 AN: 4832

European-Finnish (FIN) AF: 0.581 AC: 6135 AN: 10564

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.617 AC: 41935 AN: 67994

Other (OTH) AF: 0.611 AC: 1290 AN: 2112

Alfa AF: 0.618 Hom.: 27593

Bravo AF: 0.608

Asia WGS AF: 0.448 AC: 1559 AN: 3478

EpiCase AF: 0.624

EpiControl AF: 0.632

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	not provided (2)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.073
DANN	Benign	0.80
PhyloP100		-3.0
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: rs2228069; hg19: chr19-38956803; COSMIC: COSV62092589;