19-38433793-C-T

Variant names:

• chr19-38433793-C-T
• rs886038309
• ENST00000594335.6:n.-37C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The ENST00000594335.6(RYR1):​n.-37C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 955,918 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00032 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: RYR1 ENST00000594335.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000323 (31/96094) while in subpopulation AMR AF = 0.00385 (31/8044). AF 95% confidence interval is 0.00279. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000594335.6. 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.-37C>T		5_prime_UTR	Exon 1 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.-37C>T		5_prime_UTR	Exon 1 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000594335.6	TSL:1	n.-37C>T		non_coding_transcript_exon	Exon 1 of 103	ENSP00000470927.2
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.-37C>T		5_prime_UTR	Exon 1 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.-37C>T		5_prime_UTR	Exon 1 of 105	ENSP00000347667.3

Frequencies

GnomAD3 genomes AF: 0.000323 AC: 31 AN: 96094 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00385

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000761 AC: 19 AN: 249546 AF XY: 0.0000964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 26 AN: 859824 Hom.: 0 Cov.: 24 AF XY: 0.0000325 AC XY: 14 AN XY: 430390

African (AFR) AF: 0.00 AC: 0 AN: 19702

American (AMR) AF: 0.000848 AC: 25 AN: 29478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13354

East Asian (EAS) AF: 0.00 AC: 0 AN: 10658

South Asian (SAS) AF: 0.00 AC: 0 AN: 58098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3398

European-Non Finnish (NFE) AF: 0.00000150 AC: 1 AN: 667142

Other (OTH) AF: 0.00 AC: 0 AN: 30676

GnomAD4 genome AF: 0.000323 AC: 31 AN: 96094 Hom.: 0 Cov.: 24 AF XY: 0.000456 AC XY: 21 AN XY: 46070

African (AFR) AF: 0.00 AC: 0 AN: 25978

American (AMR) AF: 0.00385 AC: 31 AN: 8044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2372

East Asian (EAS) AF: 0.00 AC: 0 AN: 2990

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 160

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47220

Other (OTH) AF: 0.00 AC: 0 AN: 1300

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.7
DANN	Benign	0.64
PhyloP100		1.1
PromoterAI		-0.011	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886038309; hg19: chr19-38924433;