rs116130182

Variant names:

• chr19-38512425-G-A
• rs116130182
• NM_000540.3:c.9414G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38512425-G-A
• chr19-38512425-G-C
• chr19-38512425-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000540.3(RYR1):​c.9414G>A​(p.Pro3138Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,754 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (7 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -8.10
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-38512425-G-A is Benign according to our data. Variant chr19-38512425-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00439 (669/152312) while in subpopulation AFR AF = 0.0149 (621/41566). AF 95% confidence interval is 0.014. There are 3 homozygotes in GnomAd4. There are 320 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.9414G>A	p.Pro3138Pro	synonymous	Exon 63 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.9414G>A	p.Pro3138Pro	synonymous	Exon 63 of 105	NP_001036188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.9414G>A	p.Pro3138Pro	synonymous	Exon 63 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.9414G>A	p.Pro3138Pro	synonymous	Exon 63 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*157G>A		non_coding_transcript_exon	Exon 62 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 669 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00138 AC: 347 AN: 250644 AF XY: 0.00117

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000731 AC: 1068 AN: 1461442 Hom.: 7 Cov.: 34 AF XY: 0.000733 AC XY: 533 AN XY: 727092

African (AFR) AF: 0.0151 AC: 505 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52984

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000309 AC: 344 AN: 1112006

Other (OTH) AF: 0.00129 AC: 78 AN: 60388

GnomAD4 genome AF: 0.00439 AC: 669 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.00430 AC XY: 320 AN XY: 74462

African (AFR) AF: 0.0149 AC: 621 AN: 41566

American (AMR) AF: 0.00144 AC: 22 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68032

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00247 Hom.: 3

Bravo AF: 0.00490

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	-	2	not specified (2)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	not provided (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.21
DANN	Benign	0.67
PhyloP100		-8.1
Mutation Taster		=86/14	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: rs116130182; hg19: chr19-39003065;