rs115515082

chr19-38460333-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):c.2361-42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,573,574 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (132 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (96 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.742

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-38460333-A-G is Benign according to our data. Variant chr19-38460333-A-G is described in ClinVar as [Benign]. Clinvar id is 256472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.2361-42A>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.2361-42A>G		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.2361-42A>G		intron_variant		1		P4
RYR1	ENST00000599547.6	c.2361-42A>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3309 AN: 152004 Hom.: 132 Cov.: 33

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00983

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00598 AC: 1503 AN: 251226 Hom.: 69 AF XY: 0.00444 AC XY: 603 AN XY: 135782

Gnomad AFR exome AF: 0.0768

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00225 AC: 3200 AN: 1421452 Hom.: 96 Cov.: 27 AF XY: 0.00194 AC XY: 1377 AN XY: 709492

Gnomad4 AFR exome AF: 0.0719

Gnomad4 AMR exome AF: 0.00535

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.00519

GnomAD4 genome AF: 0.0218 AC: 3314 AN: 152122 Hom.: 132 Cov.: 33 AF XY: 0.0212 AC XY: 1573 AN XY: 74342

Gnomad4 AFR AF: 0.0747

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0108 Hom.: 3

Bravo AF: 0.0235

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.090
Dann	Benign	0.33

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: rs115515082; hg19: chr19-38950973;