rs2304145

Variant names:

• chr19-38440938-G-C
• rs2304145
• NM_000540.3:c.165+74G>C

Variant summary

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

The NM_000540.3(RYR1):​c.165+74G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,526,286 control chromosomes in the GnomAD database, including 183 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 0.0065 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (156 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.717
• Publications: 3 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=-0.64).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.165+74G>C		intron_variant	Intron 2 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.165+74G>C		intron_variant	Intron 2 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 982 AN: 151884 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00381

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0939

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00471

Gnomad OTH AF: 0.00481

GnomAD4 exome AF: 0.00685 AC: 9410 AN: 1374284 Hom.: 156 AF XY: 0.00673 AC XY: 4574 AN XY: 679944

African (AFR) AF: 0.00137 AC: 44 AN: 32022

American (AMR) AF: 0.00368 AC: 149 AN: 40482

Ashkenazi Jewish (ASJ) AF: 0.000447 AC: 11 AN: 24606

East Asian (EAS) AF: 0.0780 AC: 2973 AN: 38130

South Asian (SAS) AF: 0.00401 AC: 322 AN: 80320

European-Finnish (FIN) AF: 0.00198 AC: 98 AN: 49558

Middle Eastern (MID) AF: 0.00310 AC: 17 AN: 5480

European-Non Finnish (NFE) AF: 0.00499 AC: 5227 AN: 1047110

Other (OTH) AF: 0.0101 AC: 569 AN: 56576

GnomAD4 genome AF: 0.00646 AC: 982 AN: 152002 Hom.: 27 Cov.: 32 AF XY: 0.00683 AC XY: 507 AN XY: 74282

African (AFR) AF: 0.00154 AC: 64 AN: 41460

American (AMR) AF: 0.00380 AC: 58 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0941 AC: 483 AN: 5132

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4814

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10602

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00471 AC: 320 AN: 67974

Other (OTH) AF: 0.00476 AC: 10 AN: 2102

Alfa AF: 0.00434 Hom.: 1

Bravo AF: 0.00652

Asia WGS AF: 0.0310 AC: 107 AN: 3478

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	-0.64
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2304145; hg19: chr19-38931578; COSMIC: COSV62107593;