NM_000540.3:c.2168-57T>G

Variant names:

• chr19-38459089-T-G
• rs4802474
• NM_000540.3:c.2168-57T>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.2168-57T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,422,274 control chromosomes in the GnomAD database, including 289,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.62 (30138 hom., cov: 31)
  • Exomes 𝑓: 0.64 (259790 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.224
• Publications: 11 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-38459089-T-G is Benign according to our data. Variant chr19-38459089-T-G is described in ClinVar as Benign. ClinVar VariationId is 133113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.678 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.2168-57T>G		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.2168-57T>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.2168-57T>G		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.2168-57T>G		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.2168-57T>G		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94747 AN: 151896 Hom.: 30125 Cov.: 31

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.637

GnomAD4 exome AF: 0.636 AC: 807319 AN: 1270260 Hom.: 259790 AF XY: 0.630 AC XY: 404132 AN XY: 641694

African (AFR) AF: 0.528 AC: 15723 AN: 29752

American (AMR) AF: 0.687 AC: 30382 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 16559 AN: 24942

East Asian (EAS) AF: 0.647 AC: 25072 AN: 38758

South Asian (SAS) AF: 0.436 AC: 35953 AN: 82538

European-Finnish (FIN) AF: 0.694 AC: 34457 AN: 49672

Middle Eastern (MID) AF: 0.659 AC: 2542 AN: 3860

European-Non Finnish (NFE) AF: 0.649 AC: 612043 AN: 942352

Other (OTH) AF: 0.639 AC: 34588 AN: 54130

GnomAD4 genome AF: 0.624 AC: 94796 AN: 152014 Hom.: 30138 Cov.: 31 AF XY: 0.621 AC XY: 46116 AN XY: 74310

African (AFR) AF: 0.535 AC: 22183 AN: 41444

American (AMR) AF: 0.690 AC: 10533 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2324 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3071 AN: 5162

South Asian (SAS) AF: 0.419 AC: 2019 AN: 4816

European-Finnish (FIN) AF: 0.709 AC: 7501 AN: 10574

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.661 AC: 44901 AN: 67956

Other (OTH) AF: 0.632 AC: 1333 AN: 2110

Alfa AF: 0.650 Hom.: 16244

Bravo AF: 0.625

Asia WGS AF: 0.453 AC: 1578 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

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.72
PhyloP100		0.22
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4802474; hg19: chr19-38949729; COSMIC: COSV62092107;