19-38502810-G-C

Variant names:

• chr19-38502810-G-C
• rs1469696
• NM_000540.3:c.7836-70G>C

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.7836-70G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (140 hom., cov: 0)
  • Exomes 𝑓: 0.025 (538 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.121
• Publications: 2 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=-0.84).
• BP6: Variant 19-38502810-G-C is Benign according to our data. Variant chr19-38502810-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 133214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0699 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.7836-70G>C		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.7836-70G>C		intron	N/A	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.7836-70G>C		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.7836-70G>C		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.7836-70G>C		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 2711 AN: 56822 Hom.: 139 Cov.: 0

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.0511

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.0244

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.0351

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.0503

Gnomad OTH AF: 0.0484

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0249 AC: 15147 AN: 608334 Hom.: 538 Cov.: 9 AF XY: 0.0253 AC XY: 7774 AN XY: 307668

African (AFR) AF: 0.0273 AC: 273 AN: 10012

American (AMR) AF: 0.0697 AC: 1153 AN: 16546

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 321 AN: 13890

East Asian (EAS) AF: 0.0391 AC: 791 AN: 20254

South Asian (SAS) AF: 0.0265 AC: 1108 AN: 41882

European-Finnish (FIN) AF: 0.0368 AC: 589 AN: 16014

Middle Eastern (MID) AF: 0.0249 AC: 49 AN: 1964

European-Non Finnish (NFE) AF: 0.0217 AC: 10022 AN: 461514

Other (OTH) AF: 0.0320 AC: 841 AN: 26258

GnomAD4 genome AF: 0.0477 AC: 2713 AN: 56856 Hom.: 140 Cov.: 0 AF XY: 0.0481 AC XY: 1300 AN XY: 27038

African (AFR) AF: 0.0369 AC: 419 AN: 11354

American (AMR) AF: 0.0759 AC: 420 AN: 5536

Ashkenazi Jewish (ASJ) AF: 0.0244 AC: 38 AN: 1560

East Asian (EAS) AF: 0.0330 AC: 67 AN: 2028

South Asian (SAS) AF: 0.0335 AC: 50 AN: 1494

European-Finnish (FIN) AF: 0.0415 AC: 137 AN: 3302

Middle Eastern (MID) AF: 0.00877 AC: 1 AN: 114

European-Non Finnish (NFE) AF: 0.0503 AC: 1515 AN: 30130

Other (OTH) AF: 0.0481 AC: 37 AN: 770

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Aug 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.47
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism

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: rs1469696; hg19: chr19-38993450; COSMIC: COSV62102685;