19-38543746-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):c.11908-25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,611,652 control chromosomes in the GnomAD database, including 826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (87 hom., cov: 32)
  • Exomes 𝑓: 0.023 (739 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.19

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-38543746-C-G is Benign according to our data. Variant chr19-38543746-C-G is described in ClinVar as [Benign]. Clinvar id is 133024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38543746-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.11908-25C>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.11908-25C>G		intron_variant		5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3450 AN: 152162 Hom.: 86 Cov.: 32

Gnomad AFR AF: 0.00786

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0443

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0347 AC: 8626 AN: 248910 Hom.: 279 AF XY: 0.0319 AC XY: 4301 AN XY: 134724

Gnomad AFR exome AF: 0.00731

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0474

Gnomad SAS exome AF: 0.0309

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0230 AC: 33519 AN: 1459372 Hom.: 739 Cov.: 36 AF XY: 0.0227 AC XY: 16498 AN XY: 726102

Gnomad4 AFR exome AF: 0.00636

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0681

Gnomad4 SAS exome AF: 0.0293

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.0227 AC: 3453 AN: 152280 Hom.: 87 Cov.: 32 AF XY: 0.0254 AC XY: 1888 AN XY: 74454

Gnomad4 AFR AF: 0.00782

Gnomad4 AMR AF: 0.0720

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0597

Gnomad4 SAS AF: 0.0329

Gnomad4 FIN AF: 0.0443

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.00802 Hom.: 5

Bravo AF: 0.0239

Asia WGS AF: 0.0590 AC: 205 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2018	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.65
Dann	Benign	0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292797; hg19: chr19-39034386;