rs1469697

Variant names:

• chr19-38502814-A-G
• rs1469697
• NM_000540.3:c.7836-66A>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.7836-66A>G 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (682 hom., cov: 0)
  • Exomes 𝑓: 0.10 (5409 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.635
• Publications: 3 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=-0.87).
• BP6: Variant 19-38502814-A-G is Benign according to our data. Variant chr19-38502814-A-G is described in ClinVar as Benign. ClinVar VariationId is 133213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7836-66A>G		intron_variant	Intron 48 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7836-66A>G		intron_variant	Intron 48 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 9752 AN: 49360 Hom.: 679 Cov.: 0

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.173

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.207

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.103 AC: 64505 AN: 626418 Hom.: 5409 Cov.: 9 AF XY: 0.109 AC XY: 34400 AN XY: 315600

African (AFR) AF: 0.125 AC: 1284 AN: 10302

American (AMR) AF: 0.215 AC: 3877 AN: 18032

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 1685 AN: 14164

East Asian (EAS) AF: 0.144 AC: 2932 AN: 20306

South Asian (SAS) AF: 0.211 AC: 8800 AN: 41702

European-Finnish (FIN) AF: 0.136 AC: 2309 AN: 16986

Middle Eastern (MID) AF: 0.112 AC: 229 AN: 2050

European-Non Finnish (NFE) AF: 0.0840 AC: 39992 AN: 475978

Other (OTH) AF: 0.126 AC: 3397 AN: 26898

GnomAD4 genome AF: 0.198 AC: 9771 AN: 49382 Hom.: 682 Cov.: 0 AF XY: 0.199 AC XY: 4606 AN XY: 23140

African (AFR) AF: 0.193 AC: 1828 AN: 9448

American (AMR) AF: 0.246 AC: 1237 AN: 5038

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 237 AN: 1470

East Asian (EAS) AF: 0.134 AC: 213 AN: 1592

South Asian (SAS) AF: 0.236 AC: 290 AN: 1228

European-Finnish (FIN) AF: 0.129 AC: 354 AN: 2752

Middle Eastern (MID) AF: 0.186 AC: 19 AN: 102

European-Non Finnish (NFE) AF: 0.200 AC: 5311 AN: 26604

Other (OTH) AF: 0.208 AC: 142 AN: 682

Alfa AF: 0.376 Hom.: 266

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

- -

Aug 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.31
DANN	Benign	0.24
PhyloP100		-0.64
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: rs1469697; hg19: chr19-38993454; COSMIC: COSV62088836;