rs45555835

chr19-38543682-G-A

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.11907+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,612,706 control chromosomes in the GnomAD database, including 1,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (274 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1716 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.182

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=-0.85).
• BP6: Variant 19-38543682-G-A is Benign according to our data. Variant chr19-38543682-G-A is described in ClinVar as [Benign]. Clinvar id is 256413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38543682-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.11907+22G>A		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.11907+22G>A		intron_variant		5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 8267 AN: 152116 Hom.: 273 Cov.: 32

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0510

Gnomad OTH AF: 0.0614

GnomAD3 exomes AF: 0.0494 AC: 12331 AN: 249824 Hom.: 413 AF XY: 0.0493 AC XY: 6665 AN XY: 135136

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.0298

Gnomad ASJ exome AF: 0.0756

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0352

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.0509

Gnomad OTH exome AF: 0.0598

GnomAD4 exome AF: 0.0447 AC: 65282 AN: 1460472 Hom.: 1716 Cov.: 37 AF XY: 0.0449 AC XY: 32621 AN XY: 726566

Gnomad4 AFR exome AF: 0.0529

Gnomad4 AMR exome AF: 0.0333

Gnomad4 ASJ exome AF: 0.0787

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0353

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0427

Gnomad4 OTH exome AF: 0.0490

GnomAD4 genome AF: 0.0544 AC: 8274 AN: 152234 Hom.: 274 Cov.: 32 AF XY: 0.0579 AC XY: 4312 AN XY: 74424

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.0542

Gnomad4 ASJ AF: 0.0812

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0510

Gnomad4 OTH AF: 0.0603

Alfa AF: 0.0567 Hom.: 51

Bravo AF: 0.0512

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.0
Dann	Benign	0.81

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: rs45555835; hg19: chr19-39034322;