rs1469695

Variant names:

• chr19-38502732-A-G
• rs1469695
• NM_000540.3:c.7835+5A>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.7835+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,416,812 control chromosomes in the GnomAD database, including 70,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (8710 hom., cov: 20)
  • Exomes 𝑓: 0.32 (61435 hom.)
• Consequence: RYR1 NM_000540.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004438
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: 0.157
• Publications: 14 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), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), 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=-0.92).
• BP6: Variant 19-38502732-A-G is Benign according to our data. Variant chr19-38502732-A-G is described in ClinVar as Benign. ClinVar VariationId is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.7835+5A>G		splice_region intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.7835+5A>G		splice_region intron	N/A	NP_001036188.1	P21817-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.7835+5A>G		splice_region intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.7835+5A>G		splice_region intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.7835+5A>G		splice_region intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.388 AC: 47409 AN: 122054 Hom.: 8680 Cov.: 20

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.396

GnomAD2 exomes AF: 0.335 AC: 76265 AN: 227728 AF XY: 0.333

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.446

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.344

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.316 AC: 408965 AN: 1294658 Hom.: 61435 Cov.: 38 AF XY: 0.320 AC XY: 206197 AN XY: 643496

African (AFR) AF: 0.476 AC: 14307 AN: 30034

American (AMR) AF: 0.463 AC: 19166 AN: 41410

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 6878 AN: 21092

East Asian (EAS) AF: 0.444 AC: 13140 AN: 29572

South Asian (SAS) AF: 0.450 AC: 37094 AN: 82400

European-Finnish (FIN) AF: 0.398 AC: 13264 AN: 33300

Middle Eastern (MID) AF: 0.376 AC: 1918 AN: 5102

European-Non Finnish (NFE) AF: 0.285 AC: 285202 AN: 1000208

Other (OTH) AF: 0.349 AC: 17996 AN: 51540

GnomAD4 genome AF: 0.389 AC: 47491 AN: 122154 Hom.: 8710 Cov.: 20 AF XY: 0.403 AC XY: 23373 AN XY: 57968

African (AFR) AF: 0.502 AC: 16938 AN: 33752

American (AMR) AF: 0.476 AC: 5416 AN: 11376

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 920 AN: 3026

East Asian (EAS) AF: 0.416 AC: 1571 AN: 3778

South Asian (SAS) AF: 0.508 AC: 1775 AN: 3496

European-Finnish (FIN) AF: 0.416 AC: 2858 AN: 6870

Middle Eastern (MID) AF: 0.374 AC: 86 AN: 230

European-Non Finnish (NFE) AF: 0.298 AC: 17047 AN: 57200

Other (OTH) AF: 0.401 AC: 660 AN: 1646

Alfa AF: 0.322 Hom.: 4026

Bravo AF: 0.351

Asia WGS AF: 0.458 AC: 1533 AN: 3356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Malignant hyperthermia, susceptibility to, 1 (3)
-	-	2	Central core myopathy (2)
-	-	2	Congenital multicore myopathy with external ophthalmoplegia (2)
-	1	1	not provided (3)
-	-	1	King Denborough syndrome (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.1
DANN	Benign	0.42
PhyloP100		0.16
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.0020
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: rs1469695; hg19: chr19-38993372; COSMIC: COSV62089426;