19-38455575-G-C

Position:

• chr19-38455575-G-C

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.1672+29G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,611,946 control chromosomes in the GnomAD database, including 347,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31451 hom., cov: 31)
  • Exomes 𝑓: 0.66 (316420 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.0890

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=-0.81).
• BP6: Variant 19-38455575-G-C is Benign according to our data. Variant chr19-38455575-G-C is described in ClinVar as [Benign]. Clinvar id is 133107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38455575-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.1672+29G>C		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.1672+29G>C		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.1672+29G>C		intron_variant		1		P4
RYR1	ENST00000599547.6	c.1672+29G>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96909 AN: 151846 Hom.: 31441 Cov.: 31

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.801

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.654

GnomAD3 exomes AF: 0.642 AC: 161425 AN: 251250 Hom.: 52754 AF XY: 0.637 AC XY: 86438 AN XY: 135788

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.695

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.618

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.706

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.655 AC: 956796 AN: 1459982 Hom.: 316420 Cov.: 37 AF XY: 0.650 AC XY: 472408 AN XY: 726440

Gnomad4 AFR exome AF: 0.548

Gnomad4 AMR exome AF: 0.695

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.656

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.700

Gnomad4 NFE exome AF: 0.669

Gnomad4 OTH exome AF: 0.657

GnomAD4 genome AF: 0.638 AC: 96962 AN: 151964 Hom.: 31451 Cov.: 31 AF XY: 0.635 AC XY: 47171 AN XY: 74254

Gnomad4 AFR AF: 0.552

Gnomad4 AMR AF: 0.699

Gnomad4 ASJ AF: 0.701

Gnomad4 EAS AF: 0.609

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.674

Gnomad4 OTH AF: 0.648

Alfa AF: 0.617 Hom.: 3684

Bravo AF: 0.639

Asia WGS AF: 0.460 AC: 1602 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 18, 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	-0.81
CADD	Benign	6.3
DANN	Benign	0.51

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: rs2288889; hg19: chr19-38946215; COSMIC: COSV62114858;