19-38505983-T-G

Position:

• chr19-38505983-T-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.8541+37T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,536,592 control chromosomes in the GnomAD database, including 64,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8425 hom., cov: 29)
  • Exomes 𝑓: 0.26 (55949 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.510

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=-0.9).
• BP6: Variant 19-38505983-T-G is Benign according to our data. Variant chr19-38505983-T-G is described in ClinVar as [Benign]. Clinvar id is 133228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38505983-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8541+37T>G		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8541+37T>G		intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8541+37T>G		intron_variant		1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1992+37T>G		intron_variant		1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8541+37T>G		intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.329 AC: 48755 AN: 148026 Hom.: 8388 Cov.: 29

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.319 AC: 75963 AN: 238388 Hom.: 12703 AF XY: 0.319 AC XY: 41439 AN XY: 130030

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.336

Gnomad SAS exome AF: 0.456

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.263 AC: 364531 AN: 1388446 Hom.: 55949 Cov.: 32 AF XY: 0.268 AC XY: 185762 AN XY: 692798

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.335

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.284

GnomAD4 genome AF: 0.330 AC: 48854 AN: 148146 Hom.: 8425 Cov.: 29 AF XY: 0.338 AC XY: 24365 AN XY: 72140

Gnomad4 AFR AF: 0.438

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.465

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.343

Alfa AF: 0.185 Hom.: 535

Bravo AF: 0.333

Asia WGS AF: 0.484 AC: 1677 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2013

- -

Congenital multicore myopathy with external ophthalmoplegia 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

- -

Central core myopathy 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	-0.90
CADD	Benign	0.86
DANN	Benign	0.54

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: rs2960343; hg19: chr19-38996623; COSMIC: COSV62092767;