rs10406027

Variant names:

• chr19-38448768-T-C
• rs10406027
• NM_000540.3:c.1077T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-38448768-T-C
• chr19-38448768-T-G
• chr19-38448768-T-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The variant NM_000540.3:c.1077T>C in RYR1 is a synonymous (silent) variant (p.Ala359=). The filtering allele frequency (the lower threshold of the 95% CI of 19809/19952, 9835 homozygotes) of the c.1077T>C variant in RYR1 is 0.9807 for East Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). The c.1077T>C (p.Ala359=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023860/MONDO:0100150/179

• Frequency:
  • Genomes: 𝑓 0.90 (62123 hom., cov: 33)
  • Exomes 𝑓: 0.88 (564635 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:20 O:1
• Conservation: PhyloP100: -8.45
• Publications: 20 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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1077T>C	p.Ala359Ala	synonymous	Exon 11 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.1077T>C	p.Ala359Ala	synonymous	Exon 11 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.1077T>C	p.Ala359Ala	synonymous	Exon 11 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.1077T>C	p.Ala359Ala	synonymous	Exon 11 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.1077T>C		non_coding_transcript_exon	Exon 11 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137302 AN: 152164 Hom.: 62084 Cov.: 33

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.942

Gnomad AMR AF: 0.925

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.990

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.899

GnomAD2 exomes AF: 0.887 AC: 222943 AN: 251346 AF XY: 0.879

Gnomad AFR exome AF: 0.930

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.993

Gnomad FIN exome AF: 0.933

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.878 AC: 1283273 AN: 1461822 Hom.: 564635 Cov.: 66 AF XY: 0.874 AC XY: 635388 AN XY: 727210

African (AFR) AF: 0.931 AC: 31164 AN: 33478

American (AMR) AF: 0.918 AC: 41057 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 23718 AN: 26136

East Asian (EAS) AF: 0.991 AC: 39339 AN: 39700

South Asian (SAS) AF: 0.757 AC: 65286 AN: 86254

European-Finnish (FIN) AF: 0.930 AC: 49653 AN: 53412

Middle Eastern (MID) AF: 0.878 AC: 5052 AN: 5756

European-Non Finnish (NFE) AF: 0.876 AC: 974377 AN: 1111972

Other (OTH) AF: 0.888 AC: 53627 AN: 60392

GnomAD4 genome AF: 0.902 AC: 137400 AN: 152282 Hom.: 62123 Cov.: 33 AF XY: 0.903 AC XY: 67243 AN XY: 74462

African (AFR) AF: 0.933 AC: 38762 AN: 41566

American (AMR) AF: 0.925 AC: 14148 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 3143 AN: 3472

East Asian (EAS) AF: 0.990 AC: 5133 AN: 5184

South Asian (SAS) AF: 0.764 AC: 3686 AN: 4824

European-Finnish (FIN) AF: 0.938 AC: 9952 AN: 10610

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.876 AC: 59560 AN: 68006

Other (OTH) AF: 0.898 AC: 1899 AN: 2114

Alfa AF: 0.884 Hom.: 21474

Bravo AF: 0.906

Asia WGS AF: 0.874 AC: 3042 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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)
-	-	1	RYR1-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.024
DANN	Benign	0.49
PhyloP100		-8.4
Mutation Taster		=91/9	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: rs10406027; hg19: chr19-38939408; COSMIC: COSV62105060;