19-38489478-C-G

Variant names:

• chr19-38489478-C-G
• rs16972654
• NM_000540.3:c.5814+35C>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.5814+35C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,612,628 control chromosomes in the GnomAD database, including 9,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1295 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8362 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.69
• Publications: 6 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=-0.88).
• BP6: Variant 19-38489478-C-G is Benign according to our data. Variant chr19-38489478-C-G is described in ClinVar as Benign. ClinVar VariationId is 256529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.5814+35C>G		intron_variant	Intron 35 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.5814+35C>G		intron_variant	Intron 35 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18031 AN: 152072 Hom.: 1298 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0870

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0430

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0970

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.108 AC: 26711 AN: 248416 AF XY: 0.110

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0931

Gnomad ASJ exome AF: 0.0975

Gnomad EAS exome AF: 0.0353

Gnomad FIN exome AF: 0.0559

Gnomad NFE exome AF: 0.0962

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0998 AC: 145779 AN: 1460438 Hom.: 8362 Cov.: 33 AF XY: 0.103 AC XY: 74968 AN XY: 726610

African (AFR) AF: 0.191 AC: 6391 AN: 33422

American (AMR) AF: 0.0922 AC: 4124 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2699 AN: 26120

East Asian (EAS) AF: 0.0394 AC: 1564 AN: 39698

South Asian (SAS) AF: 0.203 AC: 17523 AN: 86212

European-Finnish (FIN) AF: 0.0551 AC: 2939 AN: 53348

Middle Eastern (MID) AF: 0.146 AC: 822 AN: 5636

European-Non Finnish (NFE) AF: 0.0931 AC: 103468 AN: 1110956

Other (OTH) AF: 0.104 AC: 6249 AN: 60332

GnomAD4 genome AF: 0.119 AC: 18059 AN: 152190 Hom.: 1295 Cov.: 32 AF XY: 0.117 AC XY: 8741 AN XY: 74400

African (AFR) AF: 0.183 AC: 7585 AN: 41510

American (AMR) AF: 0.0872 AC: 1333 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3470

East Asian (EAS) AF: 0.0429 AC: 222 AN: 5172

South Asian (SAS) AF: 0.214 AC: 1032 AN: 4822

European-Finnish (FIN) AF: 0.0512 AC: 543 AN: 10602

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0970 AC: 6595 AN: 68004

Other (OTH) AF: 0.131 AC: 277 AN: 2112

Alfa AF: 0.105 Hom.: 160

Bravo AF: 0.120

Asia WGS AF: 0.146 AC: 506 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 23, 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	-0.88
CADD	Benign	0.11
DANN	Benign	0.47
PhyloP100		-2.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16972654; hg19: chr19-38980118; COSMIC: COSV62097634;