19-38452790-C-T

Variant names:

• chr19-38452790-C-T
• rs35839245
• NM_000540.3:c.1245-29C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):​c.1245-29C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,550,576 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (13 hom., cov: 32)
  • Exomes 𝑓: 0.017 (249 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0330
• Publications: 3 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=-0.81).
• BP6: Variant 19-38452790-C-T is Benign according to our data. Variant chr19-38452790-C-T is described in ClinVar as Benign. ClinVar VariationId is 256421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1920/152358) while in subpopulation NFE AF = 0.0192 (1309/68032). AF 95% confidence interval is 0.0184. There are 13 homozygotes in GnomAd4. There are 918 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1245-29C>T		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.1245-29C>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.1245-29C>T		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.1245-29C>T		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.1245-29C>T		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1920 AN: 152240 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00330

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0124 AC: 1983 AN: 160528 AF XY: 0.0123

Gnomad AFR exome AF: 0.00341

Gnomad AMR exome AF: 0.00351

Gnomad ASJ exome AF: 0.00520

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0340

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0171 AC: 23931 AN: 1398218 Hom.: 249 Cov.: 32 AF XY: 0.0168 AC XY: 11605 AN XY: 689478

African (AFR) AF: 0.00233 AC: 75 AN: 32128

American (AMR) AF: 0.00459 AC: 165 AN: 35952

Ashkenazi Jewish (ASJ) AF: 0.00449 AC: 112 AN: 24918

East Asian (EAS) AF: 0.00 AC: 0 AN: 36742

South Asian (SAS) AF: 0.00566 AC: 453 AN: 80032

European-Finnish (FIN) AF: 0.0333 AC: 1605 AN: 48148

Middle Eastern (MID) AF: 0.00252 AC: 11 AN: 4364

European-Non Finnish (NFE) AF: 0.0192 AC: 20680 AN: 1078134

Other (OTH) AF: 0.0144 AC: 830 AN: 57800

GnomAD4 genome AF: 0.0126 AC: 1920 AN: 152358 Hom.: 13 Cov.: 32 AF XY: 0.0123 AC XY: 918 AN XY: 74504

African (AFR) AF: 0.00329 AC: 137 AN: 41594

American (AMR) AF: 0.00810 AC: 124 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.0278 AC: 295 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1309 AN: 68032

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00900 Hom.: 5

Bravo AF: 0.0109

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.2
DANN	Benign	0.81
PhyloP100		-0.033
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35839245; hg19: chr19-38943430;