rs7254832

Positions:

• chr19-38455211-T-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.1441-24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 1,613,088 control chromosomes in the GnomAD database, including 619,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61475 hom., cov: 30)
  • Exomes 𝑓: 0.87 (558516 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.0410

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=-0.86).
• BP6: Variant 19-38455211-T-C is Benign according to our data. Variant chr19-38455211-T-C is described in ClinVar as [Benign]. Clinvar id is 133065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38455211-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.1441-24T>C		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.1441-24T>C		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.1441-24T>C		intron_variant		1		P4
RYR1	ENST00000599547.6	c.1441-24T>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136508 AN: 152024 Hom.: 61439 Cov.: 30

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.922

Gnomad ASJ AF: 0.899

Gnomad EAS AF: 0.990

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.870

Gnomad OTH AF: 0.895

GnomAD3 exomes AF: 0.882 AC: 221876 AN: 251434 Hom.: 98387 AF XY: 0.874 AC XY: 118800 AN XY: 135894

Gnomad AFR exome AF: 0.930

Gnomad AMR exome AF: 0.914

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.992

Gnomad SAS exome AF: 0.753

Gnomad FIN exome AF: 0.922

Gnomad NFE exome AF: 0.873

Gnomad OTH exome AF: 0.895

GnomAD4 exome AF: 0.873 AC: 1275841 AN: 1460946 Hom.: 558516 Cov.: 41 AF XY: 0.869 AC XY: 631724 AN XY: 726856

Gnomad4 AFR exome AF: 0.931

Gnomad4 AMR exome AF: 0.916

Gnomad4 ASJ exome AF: 0.903

Gnomad4 EAS exome AF: 0.991

Gnomad4 SAS exome AF: 0.754

Gnomad4 FIN exome AF: 0.919

Gnomad4 NFE exome AF: 0.871

Gnomad4 OTH exome AF: 0.885

GnomAD4 genome AF: 0.898 AC: 136602 AN: 152142 Hom.: 61475 Cov.: 30 AF XY: 0.898 AC XY: 66818 AN XY: 74368

Gnomad4 AFR AF: 0.932

Gnomad4 AMR AF: 0.922

Gnomad4 ASJ AF: 0.899

Gnomad4 EAS AF: 0.990

Gnomad4 SAS AF: 0.761

Gnomad4 FIN AF: 0.927

Gnomad4 NFE AF: 0.870

Gnomad4 OTH AF: 0.895

Alfa AF: 0.878 Hom.: 68816

Bravo AF: 0.902

Asia WGS AF: 0.878 AC: 3053 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

Jan 04, 2016

- -

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	-0.86
CADD	Benign	1.6
DANN	Benign	0.30

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: rs7254832; hg19: chr19-38945851;