rs3745850

Positions:

• chr19-38469231-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000540.3(RYR1):​c.3557-74C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,605,482 control chromosomes in the GnomAD database, including 69 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 0.0023 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (59 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.57

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00235 (357/152154) while in subpopulation EAS AF= 0.0389 (201/5162). AF 95% confidence interval is 0.0345. There are 10 homozygotes in gnomad4. There are 220 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.3557-74C>T		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.3557-74C>T		intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.3557-74C>T		intron_variant		1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.3557-74C>T		intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 354 AN: 152036 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0388

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00244 AC: 3546 AN: 1453328 Hom.: 59 Cov.: 30 AF XY: 0.00308 AC XY: 2226 AN XY: 723452

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.0333

Gnomad4 SAS exome AF: 0.0208

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00235 AC: 357 AN: 152154 Hom.: 10 Cov.: 31 AF XY: 0.00296 AC XY: 220 AN XY: 74406

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0389

Gnomad4 SAS AF: 0.0249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.00178

Asia WGS AF: 0.0310 AC: 106 AN: 3478

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)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.49
DANN	Benign	0.43

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: rs3745850; hg19: chr19-38959871;