rs1469697

Positions:

• chr19-38502814-A-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.7836-66A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (682 hom., cov: 0)
  • Exomes 𝑓: 0.10 (5409 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.635

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=-0.87).
• BP6: Variant 19-38502814-A-G is Benign according to our data. Variant chr19-38502814-A-G is described in ClinVar as [Benign]. Clinvar id is 133213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502814-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7836-66A>G		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7836-66A>G		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.7836-66A>G		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1288-66A>G		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.7836-66A>G		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.198 AC: 9752 AN: 49360 Hom.: 679 Cov.: 0

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.173

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.207

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.103 AC: 64505 AN: 626418 Hom.: 5409 Cov.: 9 AF XY: 0.109 AC XY: 34400 AN XY: 315600

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.0840

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.198 AC: 9771 AN: 49382 Hom.: 682 Cov.: 0 AF XY: 0.199 AC XY: 4606 AN XY: 23140

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.208

Alfa AF: 0.376 Hom.: 266

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.31
DANN	Benign	0.24

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: rs1469697; hg19: chr19-38993454; COSMIC: COSV62088836;