NM_000540.3:c.2361-68C>T

Variant names:

• chr19-38460307-C-T
• rs2304147
• NM_000540.3:c.2361-68C>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.2361-68C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 1,398,186 control chromosomes in the GnomAD database, including 292,669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30108 hom., cov: 31)
  • Exomes 𝑓: 0.65 (262561 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.639
• 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=-0.82).
• BP6: Variant 19-38460307-C-T is Benign according to our data. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.2361-68C>T		intron_variant	Intron 19 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.2361-68C>T		intron_variant	Intron 19 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94673 AN: 151862 Hom.: 30094 Cov.: 31

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.635

GnomAD4 exome AF: 0.645 AC: 804070 AN: 1246206 Hom.: 262561 AF XY: 0.638 AC XY: 402028 AN XY: 629914

African (AFR) AF: 0.535 AC: 15547 AN: 29084

American (AMR) AF: 0.688 AC: 30503 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 16512 AN: 24762

East Asian (EAS) AF: 0.648 AC: 25083 AN: 38682

South Asian (SAS) AF: 0.434 AC: 35386 AN: 81614

European-Finnish (FIN) AF: 0.694 AC: 36981 AN: 53310

Middle Eastern (MID) AF: 0.661 AC: 3538 AN: 5352

European-Non Finnish (NFE) AF: 0.662 AC: 606116 AN: 915768

Other (OTH) AF: 0.646 AC: 34404 AN: 53282

GnomAD4 genome AF: 0.623 AC: 94722 AN: 151980 Hom.: 30108 Cov.: 31 AF XY: 0.620 AC XY: 46060 AN XY: 74282

African (AFR) AF: 0.535 AC: 22159 AN: 41434

American (AMR) AF: 0.690 AC: 10534 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2322 AN: 3466

East Asian (EAS) AF: 0.593 AC: 3060 AN: 5160

South Asian (SAS) AF: 0.416 AC: 2003 AN: 4820

European-Finnish (FIN) AF: 0.709 AC: 7489 AN: 10566

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.661 AC: 44889 AN: 67942

Other (OTH) AF: 0.630 AC: 1330 AN: 2112

Alfa AF: 0.644 Hom.: 21670

Bravo AF: 0.624

Asia WGS AF: 0.452 AC: 1574 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.78
PhyloP100		-0.64
Mutation Taster		=22/78	disease causing

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: rs2304147; hg19: chr19-38950947;