rs182004703

Variant names:

• chr19-38473637-C-A
• rs182004703
• NM_000540.3:c.4026C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38473637-C-A
• chr19-38473637-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000540.3(RYR1):​c.4026C>A​(p.Ser1342Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,560,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1342G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.42
• Publications: 2 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), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008480877).
• BP6: Variant 19-38473637-C-A is Benign according to our data. Variant chr19-38473637-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 478226.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.4026C>A	p.Ser1342Arg	missense	Exon 28 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.4026C>A	p.Ser1342Arg	missense	Exon 28 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.4026C>A	p.Ser1342Arg	missense	Exon 28 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.4026C>A	p.Ser1342Arg	missense	Exon 28 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.4026C>A		non_coding_transcript_exon	Exon 28 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151978 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000459 AC: 73 AN: 159194 AF XY: 0.000466

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00248

Gnomad NFE exome AF: 0.000456

Gnomad OTH exome AF: 0.000887

GnomAD4 exome AF: 0.000326 AC: 459 AN: 1408318 Hom.: 0 Cov.: 33 AF XY: 0.000305 AC XY: 212 AN XY: 695656

African (AFR) AF: 0.00 AC: 0 AN: 32174

American (AMR) AF: 0.00 AC: 0 AN: 36084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25206

East Asian (EAS) AF: 0.00 AC: 0 AN: 36854

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80362

European-Finnish (FIN) AF: 0.00362 AC: 178 AN: 49138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.000239 AC: 259 AN: 1084444

Other (OTH) AF: 0.000360 AC: 21 AN: 58374

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.000255 AC XY: 19 AN XY: 74366

African (AFR) AF: 0.0000723 AC: 3 AN: 41514

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67964

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000286 Hom.: 0

Bravo AF: 0.000193

ExAC AF: 0.000555 AC: 62

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.078
DANN	Benign	0.83
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0085	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.39		Gain of MoRF binding (P = 0.0104)
MVP		0.58
MPC		0.59
ClinPred		0.018	T
GERP RS		-7.9
Varity_R		0.057
gMVP		0.22
Mutation Taster		=100/0	polymorphism

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: rs182004703; hg19: chr19-38964277;