19-38548104-G-C

Variant names:

• chr19-38548104-G-C
• rs2945046
• NM_000540.3:c.12095-129G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000540.3(RYR1):​c.12095-129G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 982,350 control chromosomes in the GnomAD database, including 2,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.096 (1442 hom., cov: 31)
  • Exomes 𝑓: 0.041 (1404 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.131
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-38548104-G-C is Benign according to our data. Variant chr19-38548104-G-C is described in ClinVar as [Benign]. Clinvar id is 133031.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12095-129G>C		intron_variant	Intron 88 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12095-129G>C		intron_variant	Intron 88 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0954 AC: 14505 AN: 152070 Hom.: 1434 Cov.: 31

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0683

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0341

Gnomad OTH AF: 0.0746

GnomAD4 exome AF: 0.0407 AC: 33757 AN: 830162 Hom.: 1404 AF XY: 0.0389 AC XY: 16698 AN XY: 429628

African (AFR) AF: 0.254 AC: 5357 AN: 21054

American (AMR) AF: 0.0945 AC: 3334 AN: 35266

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 828 AN: 21580

East Asian (EAS) AF: 0.0000897 AC: 3 AN: 33450

South Asian (SAS) AF: 0.0234 AC: 1594 AN: 68092

European-Finnish (FIN) AF: 0.0484 AC: 1889 AN: 39030

Middle Eastern (MID) AF: 0.0341 AC: 104 AN: 3048

European-Non Finnish (NFE) AF: 0.0328 AC: 18686 AN: 569226

Other (OTH) AF: 0.0498 AC: 1962 AN: 39416

GnomAD4 genome AF: 0.0956 AC: 14554 AN: 152188 Hom.: 1442 Cov.: 31 AF XY: 0.0933 AC XY: 6938 AN XY: 74402

African (AFR) AF: 0.251 AC: 10399 AN: 41486

American (AMR) AF: 0.0687 AC: 1049 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4830

European-Finnish (FIN) AF: 0.0362 AC: 384 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0341 AC: 2318 AN: 68006

Other (OTH) AF: 0.0739 AC: 156 AN: 2112

Alfa AF: 0.0704 Hom.: 100

Bravo AF: 0.106

Asia WGS AF: 0.0300 AC: 107 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.63
PhyloP100		0.13
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: rs2945046; hg19: chr19-39038744;