NM_000540.3:c.9472+30C>T

Variant names:

• chr19-38512513-C-T
• rs77374921
• NM_000540.3:c.9472+30C>T

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.9472+30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,598,026 control chromosomes in the GnomAD database, including 3,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (281 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3464 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.49
• Publications: 5 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=-0.95).
• BP6: Variant 19-38512513-C-T is Benign according to our data. Variant chr19-38512513-C-T is described in ClinVar as [Benign]. Clinvar id is 256583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.9472+30C>T		intron_variant	Intron 63 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.9472+30C>T		intron_variant	Intron 63 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8366 AN: 152176 Hom.: 281 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0630

GnomAD2 exomes AF: 0.0671 AC: 16140 AN: 240568 AF XY: 0.0699

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.0711

Gnomad ASJ exome AF: 0.0478

Gnomad EAS exome AF: 0.00262

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0662

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0660 AC: 95448 AN: 1445732 Hom.: 3464 Cov.: 32 AF XY: 0.0678 AC XY: 48781 AN XY: 719978

African (AFR) AF: 0.0342 AC: 1142 AN: 33364

American (AMR) AF: 0.0677 AC: 3027 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 1316 AN: 26094

East Asian (EAS) AF: 0.0123 AC: 486 AN: 39658

South Asian (SAS) AF: 0.118 AC: 10171 AN: 86148

European-Finnish (FIN) AF: 0.0812 AC: 3517 AN: 43290

Middle Eastern (MID) AF: 0.0697 AC: 401 AN: 5750

European-Non Finnish (NFE) AF: 0.0648 AC: 71744 AN: 1106596

Other (OTH) AF: 0.0606 AC: 3644 AN: 60120

GnomAD4 genome AF: 0.0550 AC: 8372 AN: 152294 Hom.: 281 Cov.: 32 AF XY: 0.0568 AC XY: 4227 AN XY: 74468

African (AFR) AF: 0.0341 AC: 1416 AN: 41562

American (AMR) AF: 0.0476 AC: 728 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3472

East Asian (EAS) AF: 0.00637 AC: 33 AN: 5184

South Asian (SAS) AF: 0.119 AC: 573 AN: 4826

European-Finnish (FIN) AF: 0.0857 AC: 910 AN: 10616

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0639 AC: 4347 AN: 68016

Other (OTH) AF: 0.0633 AC: 134 AN: 2116

Alfa AF: 0.0572 Hom.: 55

Bravo AF: 0.0501

Asia WGS AF: 0.0690 AC: 240 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 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 28, 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	-0.95
CADD	Benign	0.019
DANN	Benign	0.67
PhyloP100		-5.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77374921; hg19: chr19-39003153; COSMIC: COSV62114812;