rs10500279

chr19-38544428-G-C

Variant summary

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

The NM_000540.3(RYR1):c.12012+553G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 152,202 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.059 (399 hom., cov: 32)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.471

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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.12012+553G>C		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.12012+553G>C		intron_variant		5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.0593 AC: 9025 AN: 152084 Hom.: 397 Cov.: 32

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0626

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0506

Gnomad OTH AF: 0.0603

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0594 AC: 9044 AN: 152202 Hom.: 399 Cov.: 32 AF XY: 0.0621 AC XY: 4621 AN XY: 74418

Gnomad4 AFR AF: 0.0482

Gnomad4 AMR AF: 0.0622

Gnomad4 ASJ AF: 0.0626

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.0269

Gnomad4 NFE AF: 0.0506

Gnomad4 OTH AF: 0.0663

Alfa AF: 0.0472 Hom.: 23

Bravo AF: 0.0572

Asia WGS AF: 0.225 AC: 782 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.1
Dann	Benign	0.64

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: rs10500279; hg19: chr19-39035068;