NM_000540.3:c.12869C>T

Variant names:

• chr19-38565203-C-T
• rs755065800
• NM_000540.3:c.12869C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000540.3(RYR1):​c.12869C>T​(p.Ala4290Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000676 in 1,005,642 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.397
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0445036).
• BP6: Variant 19-38565203-C-T is Benign according to our data. Variant chr19-38565203-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 544505.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00271 (397/146552) while in subpopulation AFR AF = 0.00909 (372/40902). AF 95% confidence interval is 0.00833. There are 1 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.12869C>T	p.Ala4290Val	missense	Exon 91 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.12854C>T	p.Ala4285Val	missense	Exon 90 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.12869C>T	p.Ala4290Val	missense	Exon 91 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.12854C>T	p.Ala4285Val	missense	Exon 90 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*3579C>T		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 396 AN: 146446 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000814

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000759

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00 AC: 0 AN: 550 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000329 AC: 283 AN: 859090 Hom.: 2 Cov.: 30 AF XY: 0.000338 AC XY: 135 AN XY: 399468

African (AFR) AF: 0.0106 AC: 173 AN: 16292

American (AMR) AF: 0.00107 AC: 2 AN: 1862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5766

East Asian (EAS) AF: 0.00 AC: 0 AN: 4726

South Asian (SAS) AF: 0.000913 AC: 16 AN: 17530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3262

Middle Eastern (MID) AF: 0.00400 AC: 7 AN: 1748

European-Non Finnish (NFE) AF: 0.0000744 AC: 58 AN: 779154

Other (OTH) AF: 0.000939 AC: 27 AN: 28750

GnomAD4 genome AF: 0.00271 AC: 397 AN: 146552 Hom.: 1 Cov.: 32 AF XY: 0.00277 AC XY: 198 AN XY: 71354

African (AFR) AF: 0.00909 AC: 372 AN: 40902

American (AMR) AF: 0.000813 AC: 12 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000759 AC: 5 AN: 65884

Other (OTH) AF: 0.00197 AC: 4 AN: 2034

Alfa AF: 0.00214 Hom.: 0

ExAC AF: 0.00255 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	RYR1-related disorder (2)
-	1	-	King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.26	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.045	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.40
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.27
Sift	Benign	0.62	T
Polyphen		0.39	B
Vest4		0.15
MutPred		0.33		Gain of MoRF binding (P = 0.0714)
MVP		0.82
MPC		0.73
ClinPred		0.070	T
GERP RS		-2.3
PromoterAI		-0.037	Neutral
Varity_R		0.072
gMVP		0.32
Mutation Taster		=63/37	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: rs755065800; hg19: chr19-39055843;