rs7254832

Variant names:

• chr19-38455211-T-C
• rs7254832
• NM_000540.3:c.1441-24T>C

Variant summary

Our verdict is Benign. The variant received -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:6 O:1
• Conservation: PhyloP100: -0.0410
• Publications: 15 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 133065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.1441-24T>C		intron_variant	Intron 13 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1441-24T>C		intron_variant	Intron 13 of 105	5	NM_000540.3	ENSP00000352608.2

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

GnomAD2 exomes AF: 0.882 AC: 221876 AN: 251434 AF XY: 0.874

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 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

African (AFR) AF: 0.931 AC: 31163 AN: 33464

American (AMR) AF: 0.916 AC: 40943 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 23598 AN: 26128

East Asian (EAS) AF: 0.991 AC: 39323 AN: 39700

South Asian (SAS) AF: 0.754 AC: 65036 AN: 86232

European-Finnish (FIN) AF: 0.919 AC: 49054 AN: 53370

Middle Eastern (MID) AF: 0.871 AC: 5020 AN: 5764

European-Non Finnish (NFE) AF: 0.871 AC: 968299 AN: 1111210

Other (OTH) AF: 0.885 AC: 53405 AN: 60358

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

African (AFR) AF: 0.932 AC: 38684 AN: 41496

American (AMR) AF: 0.922 AC: 14079 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 3120 AN: 3472

East Asian (EAS) AF: 0.990 AC: 5127 AN: 5180

South Asian (SAS) AF: 0.761 AC: 3661 AN: 4810

European-Finnish (FIN) AF: 0.927 AC: 9838 AN: 10612

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.870 AC: 59143 AN: 67984

Other (OTH) AF: 0.895 AC: 1886 AN: 2108

Alfa AF: 0.881 Hom.: 107632

Bravo AF: 0.902

Asia WGS AF: 0.878 AC: 3053 AN: 3478

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Benign:1

Jan 04, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

King Denborough syndrome Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.30
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7254832; hg19: chr19-38945851;