NM_000540.3:c.7926+28A>G

Variant names:

• chr19-38502998-A-G
• rs1469699
• NM_000540.3:c.7926+28A>G

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.7926+28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,598,578 control chromosomes in the GnomAD database, including 72,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10022 hom., cov: 31)
  • Exomes 𝑓: 0.29 (62898 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.51
• Publications: 7 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=-0.85).
• BP6: Variant 19-38502998-A-G is Benign according to our data. Variant chr19-38502998-A-G is described in ClinVar as Benign. ClinVar VariationId is 133216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.7926+28A>G		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.7926+28A>G		intron	N/A	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.7926+28A>G		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.7926+28A>G		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.7926+28A>G		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52935 AN: 151798 Hom.: 9983 Cov.: 31

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.337 AC: 81492 AN: 241472 AF XY: 0.335

Gnomad AFR exome AF: 0.486

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.346

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.264

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.287 AC: 414744 AN: 1446662 Hom.: 62898 Cov.: 34 AF XY: 0.291 AC XY: 209244 AN XY: 720132

African (AFR) AF: 0.480 AC: 16052 AN: 33414

American (AMR) AF: 0.437 AC: 19467 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6936 AN: 26106

East Asian (EAS) AF: 0.341 AC: 13520 AN: 39602

South Asian (SAS) AF: 0.440 AC: 37815 AN: 85952

European-Finnish (FIN) AF: 0.313 AC: 13577 AN: 43368

Middle Eastern (MID) AF: 0.343 AC: 1972 AN: 5756

European-Non Finnish (NFE) AF: 0.259 AC: 287050 AN: 1107800

Other (OTH) AF: 0.305 AC: 18355 AN: 60132

GnomAD4 genome AF: 0.349 AC: 53037 AN: 151916 Hom.: 10022 Cov.: 31 AF XY: 0.356 AC XY: 26451 AN XY: 74264

African (AFR) AF: 0.477 AC: 19758 AN: 41390

American (AMR) AF: 0.394 AC: 6018 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 945 AN: 3470

East Asian (EAS) AF: 0.368 AC: 1896 AN: 5158

South Asian (SAS) AF: 0.450 AC: 2167 AN: 4818

European-Finnish (FIN) AF: 0.314 AC: 3313 AN: 10556

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17866 AN: 67946

Other (OTH) AF: 0.353 AC: 743 AN: 2102

Alfa AF: 0.298 Hom.: 4688

Bravo AF: 0.358

Asia WGS AF: 0.492 AC: 1709 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

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Oct 25, 2013

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.25
DANN	Benign	0.38
PhyloP100		-1.5
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: rs1469699; hg19: chr19-38993638; COSMIC: COSV62091654;