chr19-38505459-C-T

Position:

• chr19-38505459-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.8400+61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,224,474 control chromosomes in the GnomAD database, including 1,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (700 hom., cov: 31)
  • Exomes 𝑓: 0.033 (989 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.262

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=-0.87).
• BP6: Variant 19-38505459-C-T is Benign according to our data. Variant chr19-38505459-C-T is described in ClinVar as [Benign]. Clinvar id is 133225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38505459-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8400+61C>T		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8400+61C>T		intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8400+61C>T		intron_variant		1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1851+61C>T		intron_variant		1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8400+61C>T		intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10482 AN: 152100 Hom.: 696 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0618

GnomAD4 exome AF: 0.0333 AC: 35750 AN: 1072256 Hom.: 989 AF XY: 0.0322 AC XY: 17511 AN XY: 543944

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.0885

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.0000863

Gnomad4 SAS exome AF: 0.0205

Gnomad4 FIN exome AF: 0.0135

Gnomad4 NFE exome AF: 0.0303

Gnomad4 OTH exome AF: 0.0401

GnomAD4 genome AF: 0.0691 AC: 10522 AN: 152218 Hom.: 700 Cov.: 31 AF XY: 0.0671 AC XY: 4998 AN XY: 74444

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0714

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.00913

Gnomad4 NFE AF: 0.0298

Gnomad4 OTH AF: 0.0611

Alfa AF: 0.0488 Hom.: 50

Bravo AF: 0.0799

Asia WGS AF: 0.0220 AC: 78 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.3
DANN	Benign	0.53

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: rs2960341; hg19: chr19-38996099; COSMIC: COSV62114020;