chr19-38543746-C-G

Variant names:

• chr19-38543746-C-G
• rs2292797
• NM_000540.3:c.11908-25C>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.11908-25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,611,652 control chromosomes in the GnomAD database, including 826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (87 hom., cov: 32)
  • Exomes 𝑓: 0.023 (739 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.19
• Publications: 4 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 19-38543746-C-G is Benign according to our data. Variant chr19-38543746-C-G is described in ClinVar as Benign. ClinVar VariationId is 133024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.11908-25C>G		intron_variant	Intron 86 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.11908-25C>G		intron_variant	Intron 86 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3450 AN: 152162 Hom.: 86 Cov.: 32

Gnomad AFR AF: 0.00786

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0443

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0347 AC: 8626 AN: 248910 AF XY: 0.0319

Gnomad AFR exome AF: 0.00731

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0474

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0230 AC: 33519 AN: 1459372 Hom.: 739 Cov.: 36 AF XY: 0.0227 AC XY: 16498 AN XY: 726102

African (AFR) AF: 0.00636 AC: 213 AN: 33474

American (AMR) AF: 0.109 AC: 4860 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26134

East Asian (EAS) AF: 0.0681 AC: 2705 AN: 39700

South Asian (SAS) AF: 0.0293 AC: 2531 AN: 86240

European-Finnish (FIN) AF: 0.0441 AC: 2251 AN: 51038

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5766

European-Non Finnish (NFE) AF: 0.0173 AC: 19255 AN: 1111962

Other (OTH) AF: 0.0264 AC: 1592 AN: 60366

GnomAD4 genome AF: 0.0227 AC: 3453 AN: 152280 Hom.: 87 Cov.: 32 AF XY: 0.0254 AC XY: 1888 AN XY: 74454

African (AFR) AF: 0.00782 AC: 325 AN: 41574

American (AMR) AF: 0.0720 AC: 1101 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0597 AC: 309 AN: 5178

South Asian (SAS) AF: 0.0329 AC: 159 AN: 4826

European-Finnish (FIN) AF: 0.0443 AC: 470 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1032 AN: 68008

Other (OTH) AF: 0.0237 AC: 50 AN: 2110

Alfa AF: 0.00802 Hom.: 5

Bravo AF: 0.0239

Asia WGS AF: 0.0590 AC: 205 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 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

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 29, 2013

PreventionGenetics, part of Exact Sciences

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	0.65
DANN	Benign	0.25
PhyloP100		-1.2
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: rs2292797; hg19: chr19-39034386;