rs908644

chr19-38528088-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000540.3(RYR1):c.10825-218C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 632,186 control chromosomes in the GnomAD database, including 11,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4233 hom., cov: 31)
  • Exomes 𝑓: 0.17 (7649 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.204

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-38528088-C-G is Benign according to our data. Variant chr19-38528088-C-G is described in ClinVar as [Benign]. Clinvar id is 133000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-38528088-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10825-218C>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10825-218C>G		intron_variant		5	NM_000540.3	A2
	ENST00000597015.1	n.235+233G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32756 AN: 151604 Hom.: 4215 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.185 AC: 13159 AN: 71204 Hom.: 1473 AF XY: 0.183 AC XY: 6726 AN XY: 36738

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.164

Gnomad SAS exome AF: 0.289

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.168 AC: 80532 AN: 480464 Hom.: 7649 Cov.: 5 AF XY: 0.172 AC XY: 43965 AN XY: 255524

Gnomad4 AFR exome AF: 0.372

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.216 AC: 32824 AN: 151722 Hom.: 4233 Cov.: 31 AF XY: 0.220 AC XY: 16302 AN XY: 74178

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.215

Alfa AF: 0.178 Hom.: 388

Bravo AF: 0.220

Asia WGS AF: 0.286 AC: 995 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
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	-0.97
Cadd	Benign	1.7
Dann	Benign	0.60

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: rs908644; hg19: chr19-39018728;