19-38506436-C-T

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.8617-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,498 control chromosomes in the GnomAD database, including 67,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8640 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58949 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.191

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=-0.8).
• BP6: Variant 19-38506436-C-T is Benign according to our data. Variant chr19-38506436-C-T is described in ClinVar as [Benign]. Clinvar id is 133231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38506436-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.8617-35C>T		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.8617-35C>T		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.8617-35C>T		intron_variant		1		P4
RYR1	ENST00000594335.5	c.2069-35C>T		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.8617-35C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49485 AN: 151856 Hom.: 8604 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.332

GnomAD3 exomes AF: 0.322 AC: 80829 AN: 251312 Hom.: 13985 AF XY: 0.321 AC XY: 43664 AN XY: 135862

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.276 AC: 403163 AN: 1461522 Hom.: 58949 Cov.: 36 AF XY: 0.280 AC XY: 203846 AN XY: 727080

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.326 AC: 49582 AN: 151976 Hom.: 8640 Cov.: 31 AF XY: 0.333 AC XY: 24770 AN XY: 74290

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.362

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.337

Alfa AF: 0.190 Hom.: 572

Bravo AF: 0.333

Asia WGS AF: 0.487 AC: 1692 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2013

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Central core myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.7
Dann	Benign	0.71

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: rs2960344; hg19: chr19-38997076; COSMIC: COSV62092509;