19-38523042-C-G

Variant names:

• chr19-38523042-C-G
• rs150977342
• NM_000540.3:c.10274C>G

Variant summary

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

The NM_000540.3(RYR1):​c.10274C>G​(p.Thr3425Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,138 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3425M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.10274C>G	p.Thr3425Arg	missense	Exon 68 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.10274C>G	p.Thr3425Arg	missense	Exon 68 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.10274C>G	p.Thr3425Arg	missense	Exon 68 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.10274C>G	p.Thr3425Arg	missense	Exon 68 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*1017C>G		non_coding_transcript_exon	Exon 67 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000262 AC: 6 AN: 229004 AF XY: 0.00000802

Gnomad AFR exome AF: 0.000212

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450138 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 720624

African (AFR) AF: 0.00 AC: 0 AN: 33250

American (AMR) AF: 0.00 AC: 0 AN: 42536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39328

South Asian (SAS) AF: 0.00 AC: 0 AN: 85072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107710

Other (OTH) AF: 0.0000334 AC: 2 AN: 59862

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.10	N
PhyloP100		2.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.15	N
REVEL	Uncertain	0.46
Sift	Benign	0.29	T
Polyphen		0.82	P
Vest4		0.70
MutPred		0.17		Gain of solvent accessibility (P = 0.0503)
MVP		0.95
MPC		0.35
ClinPred		0.063	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.44
Mutation Taster		=12/88	disease causing

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: rs150977342; hg19: chr19-39013682;