rs3829976

Positions:

• chr19-38505179-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000540.3(RYR1):​c.8310+98C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,241,828 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.019 (63 hom., cov: 31)
  • Exomes 𝑓: 0.020 (395 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.707

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.8310+98C>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.8310+98C>G		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.8310+98C>G		intron_variant		1		P4
RYR1	ENST00000594335.5	c.1762+98C>G		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.8310+98C>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2822 AN: 151906 Hom.: 62 Cov.: 31

Gnomad AFR AF: 0.00440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0588

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0473

Gnomad SAS AF: 0.00584

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0197 AC: 21430 AN: 1089804 Hom.: 395 Cov.: 15 AF XY: 0.0189 AC XY: 10483 AN XY: 555694

Gnomad4 AFR exome AF: 0.00396

Gnomad4 AMR exome AF: 0.0818

Gnomad4 ASJ exome AF: 0.00179

Gnomad4 EAS exome AF: 0.0507

Gnomad4 SAS exome AF: 0.00541

Gnomad4 FIN exome AF: 0.0406

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0225

GnomAD4 genome AF: 0.0186 AC: 2825 AN: 152024 Hom.: 63 Cov.: 31 AF XY: 0.0208 AC XY: 1545 AN XY: 74318

Gnomad4 AFR AF: 0.00439

Gnomad4 AMR AF: 0.0590

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0472

Gnomad4 SAS AF: 0.00564

Gnomad4 FIN AF: 0.0415

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.0169 Hom.: 5

Bravo AF: 0.0193

Asia WGS AF: 0.0390 AC: 136 AN: 3476

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.1
DANN	Benign	0.82

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: rs3829976; hg19: chr19-38995819; COSMIC: COSV62102570;