rs142518033

Variant names:

• chr19-38536027-G-A
• rs142518033
• NM_000540.3:c.11547G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):​c.11547G>A​(p.Gln3849Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.0191 in 1,613,838 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 31)
  • Exomes 𝑓: 0.019 (328 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 4.19
• Publications: 5 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

ENSG00000268055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-38536027-G-A is Benign according to our data. Variant chr19-38536027-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0157 (2382/152200) while in subpopulation NFE AF = 0.0212 (1442/67996). AF 95% confidence interval is 0.0203. There are 33 homozygotes in GnomAd4. There are 1183 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.11547G>A	p.Gln3849Gln	synonymous	Exon 82 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.11532G>A	p.Gln3844Gln	synonymous	Exon 81 of 105	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.11547G>A	p.Gln3849Gln	synonymous	Exon 82 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.11532G>A	p.Gln3844Gln	synonymous	Exon 81 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*2275G>A		non_coding_transcript_exon	Exon 80 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2384 AN: 152082 Hom.: 33 Cov.: 31

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0168 AC: 4218 AN: 250860 AF XY: 0.0173

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00843

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0226

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0195 AC: 28453 AN: 1461638 Hom.: 328 Cov.: 32 AF XY: 0.0194 AC XY: 14088 AN XY: 727100

African (AFR) AF: 0.00329 AC: 110 AN: 33480

American (AMR) AF: 0.00940 AC: 420 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 721 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00611 AC: 527 AN: 86188

European-Finnish (FIN) AF: 0.0345 AC: 1842 AN: 53358

Middle Eastern (MID) AF: 0.0213 AC: 123 AN: 5766

European-Non Finnish (NFE) AF: 0.0213 AC: 23732 AN: 1111938

Other (OTH) AF: 0.0162 AC: 976 AN: 60388

GnomAD4 genome AF: 0.0157 AC: 2382 AN: 152200 Hom.: 33 Cov.: 31 AF XY: 0.0159 AC XY: 1183 AN XY: 74404

African (AFR) AF: 0.00380 AC: 158 AN: 41532

American (AMR) AF: 0.0122 AC: 186 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4830

European-Finnish (FIN) AF: 0.0375 AC: 397 AN: 10590

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1442 AN: 67996

Other (OTH) AF: 0.0185 AC: 39 AN: 2106

Alfa AF: 0.0182 Hom.: 17

Bravo AF: 0.0132

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0254

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (5)
-	-	3	Malignant hyperthermia, susceptibility to, 1 (3)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (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	-0.44
CADD	Benign	8.9
DANN	Benign	0.68
PhyloP100		4.2
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: rs142518033; hg19: chr19-39026667;