19-38453088-G-C

Variant names:

• chr19-38453088-G-C
• rs12460768
• NM_000540.3:c.1440+74G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000540.3(RYR1):​c.1440+74G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,493,130 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 28)
  • Exomes 𝑓: 0.0027 (29 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.86
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00224 (338/151198) while in subpopulation SAS AF = 0.00775 (37/4772). AF 95% confidence interval is 0.00578. There are 2 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD 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.1440+74G>C		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.1440+74G>C		intron	N/A	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.1440+74G>C		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.1440+74G>C		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.1440+74G>C		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 339 AN: 151082 Hom.: 2 Cov.: 28

Gnomad AFR AF: 0.000439

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00775

Gnomad FIN AF: 0.00248

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00337

GnomAD4 exome AF: 0.00266 AC: 3568 AN: 1341932 Hom.: 29 AF XY: 0.00291 AC XY: 1945 AN XY: 668050

African (AFR) AF: 0.000514 AC: 16 AN: 31126

American (AMR) AF: 0.000510 AC: 20 AN: 39204

Ashkenazi Jewish (ASJ) AF: 0.000202 AC: 5 AN: 24726

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37766

South Asian (SAS) AF: 0.00913 AC: 736 AN: 80634

European-Finnish (FIN) AF: 0.00172 AC: 83 AN: 48210

Middle Eastern (MID) AF: 0.00363 AC: 17 AN: 4678

European-Non Finnish (NFE) AF: 0.00252 AC: 2571 AN: 1019514

Other (OTH) AF: 0.00212 AC: 119 AN: 56074

GnomAD4 genome AF: 0.00224 AC: 338 AN: 151198 Hom.: 2 Cov.: 28 AF XY: 0.00226 AC XY: 167 AN XY: 73804

African (AFR) AF: 0.000438 AC: 18 AN: 41136

American (AMR) AF: 0.00105 AC: 16 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00775 AC: 37 AN: 4772

European-Finnish (FIN) AF: 0.00248 AC: 26 AN: 10470

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00340 AC: 230 AN: 67726

Other (OTH) AF: 0.00333 AC: 7 AN: 2100

Alfa AF: 0.00257 Hom.: 1495

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.36
DANN	Benign	0.46
PhyloP100		-2.9
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: rs12460768; hg19: chr19-38943728;