rs3745852

chr19-38499306-G-A

Variant summary

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

The NM_000540.3(RYR1):c.7027+63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,611,672 control chromosomes in the GnomAD database, including 231 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 0.0075 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (200 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.86

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7027+63G>A		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7027+63G>A		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7027+63G>A		intron_variant		1		P4
RYR1	ENST00000594335.5	c.479+63G>A		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.7027+63G>A		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1148 AN: 152192 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0689

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.00493 AC: 7195 AN: 1459362 Hom.: 200 AF XY: 0.00522 AC XY: 3787 AN XY: 726108

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.0409

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0729

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.000358

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.00718

GnomAD4 genome AF: 0.00754 AC: 1148 AN: 152310 Hom.: 31 Cov.: 32 AF XY: 0.00924 AC XY: 688 AN XY: 74466

Gnomad4 AFR AF: 0.00139

Gnomad4 AMR AF: 0.0365

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0689

Gnomad4 SAS AF: 0.0263

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00251 Hom.: 11

Bravo AF: 0.00997

Asia WGS AF: 0.0540 AC: 188 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	-0.90
Cadd	Benign	0.055
Dann	Benign	0.68

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: rs3745852; hg19: chr19-38989946; COSMIC: COSV62088010;