rs3829976

Variant names:

• chr19-38505179-C-G
• rs3829976
• NM_000540.3:c.8310+98C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000540.3(RYR1):​c.8310+98C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,241,828 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.019 (63 hom., cov: 31)
  • Exomes 𝑓: 0.020 (395 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.707
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8310+98C>G		intron_variant	Intron 52 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8310+98C>G		intron_variant	Intron 52 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2822 AN: 151906 Hom.: 62 Cov.: 31

Gnomad AFR AF: 0.00440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0588

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0473

Gnomad SAS AF: 0.00584

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0197 AC: 21430 AN: 1089804 Hom.: 395 Cov.: 15 AF XY: 0.0189 AC XY: 10483 AN XY: 555694

African (AFR) AF: 0.00396 AC: 101 AN: 25496

American (AMR) AF: 0.0818 AC: 3259 AN: 39824

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 42 AN: 23498

East Asian (EAS) AF: 0.0507 AC: 1852 AN: 36548

South Asian (SAS) AF: 0.00541 AC: 412 AN: 76220

European-Finnish (FIN) AF: 0.0406 AC: 2094 AN: 51574

Middle Eastern (MID) AF: 0.00212 AC: 9 AN: 4250

European-Non Finnish (NFE) AF: 0.0160 AC: 12578 AN: 784366

Other (OTH) AF: 0.0225 AC: 1083 AN: 48028

GnomAD4 genome AF: 0.0186 AC: 2825 AN: 152024 Hom.: 63 Cov.: 31 AF XY: 0.0208 AC XY: 1545 AN XY: 74318

African (AFR) AF: 0.00439 AC: 182 AN: 41454

American (AMR) AF: 0.0590 AC: 901 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.0472 AC: 243 AN: 5150

South Asian (SAS) AF: 0.00564 AC: 27 AN: 4790

European-Finnish (FIN) AF: 0.0415 AC: 440 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0145 AC: 985 AN: 67976

Other (OTH) AF: 0.0209 AC: 44 AN: 2110

Alfa AF: 0.0169 Hom.: 5

Bravo AF: 0.0193

Asia WGS AF: 0.0390 AC: 136 AN: 3476

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.1
DANN	Benign	0.82
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism

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: rs3829976; hg19: chr19-38995819; COSMIC: COSV62102570;