chr19-38512051-C-T

Variant names:

• chr19-38512051-C-T
• rs2960338
• NM_000540.3:c.9173-21C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.9173-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,609,982 control chromosomes in the GnomAD database, including 14,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2277 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12095 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.783
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-38512051-C-T is Benign according to our data. Variant chr19-38512051-C-T is described in ClinVar as Benign. ClinVar VariationId is 133238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

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.9173-21C>T		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.9173-21C>T		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.9173-21C>T		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.9173-21C>T		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.9123-21C>T		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23868 AN: 151982 Hom.: 2265 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.0667

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.141 AC: 34763 AN: 246912 AF XY: 0.136

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.0760

Gnomad EAS exome AF: 0.0528

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.122 AC: 178235 AN: 1457882 Hom.: 12095 Cov.: 33 AF XY: 0.123 AC XY: 88846 AN XY: 725102

African (AFR) AF: 0.251 AC: 8371 AN: 33348

American (AMR) AF: 0.244 AC: 10779 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.0809 AC: 2110 AN: 26068

East Asian (EAS) AF: 0.0831 AC: 3296 AN: 39646

South Asian (SAS) AF: 0.159 AC: 13603 AN: 85684

European-Finnish (FIN) AF: 0.137 AC: 7297 AN: 53272

Middle Eastern (MID) AF: 0.108 AC: 625 AN: 5764

European-Non Finnish (NFE) AF: 0.112 AC: 124498 AN: 1109614

Other (OTH) AF: 0.127 AC: 7656 AN: 60256

GnomAD4 genome AF: 0.157 AC: 23921 AN: 152100 Hom.: 2277 Cov.: 32 AF XY: 0.159 AC XY: 11816 AN XY: 74332

African (AFR) AF: 0.252 AC: 10447 AN: 41450

American (AMR) AF: 0.186 AC: 2837 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 301 AN: 3472

East Asian (EAS) AF: 0.0667 AC: 345 AN: 5172

South Asian (SAS) AF: 0.163 AC: 787 AN: 4822

European-Finnish (FIN) AF: 0.137 AC: 1451 AN: 10594

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7381 AN: 67986

Other (OTH) AF: 0.157 AC: 332 AN: 2112

Alfa AF: 0.130 Hom.: 2265

Bravo AF: 0.166

Asia WGS AF: 0.149 AC: 518 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.44
DANN	Benign	0.56
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

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: rs2960338; hg19: chr19-39002691; COSMIC: COSV62108116;