chr19-38565576-C-A

Variant names:

• chr19-38565576-C-A
• rs994374423
• NM_000540.3:c.13242C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000540.3(RYR1):​c.13242C>A​(p.Asp4414Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.94
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1613706).

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.13242C>A	p.Asp4414Glu	missense	Exon 91 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.13227C>A	p.Asp4409Glu	missense	Exon 90 of 105	NP_001036188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.13242C>A	p.Asp4414Glu	missense	Exon 91 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.13227C>A	p.Asp4409Glu	missense	Exon 90 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*3952C>A		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1320058 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 650336

African (AFR) AF: 0.00 AC: 0 AN: 26800

American (AMR) AF: 0.00 AC: 0 AN: 27352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22764

East Asian (EAS) AF: 0.00 AC: 0 AN: 29170

South Asian (SAS) AF: 0.00 AC: 0 AN: 71702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3884

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050732

Other (OTH) AF: 0.00 AC: 0 AN: 54890

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.13
DANN	Benign	0.77
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.1	L
PhyloP100		-5.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.24
Sift	Benign	0.73	T
Polyphen		0.0050	B
Vest4		0.084
MutPred		0.33		Loss of glycosylation at S4409 (P = 0.2208)
MVP		0.68
MPC		0.53
ClinPred		0.046	T
GERP RS		-4.4
PromoterAI		-0.041	Neutral
Varity_R		0.034
gMVP		0.26
Mutation Taster		=75/25	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: rs994374423; hg19: chr19-39056216;