19-38502916-C-T

Variant names:

• chr19-38502916-C-T
• rs1469698
• NM_000540.3:c.7872C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.7872C>T​(p.Arg2624Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,611,386 control chromosomes in the GnomAD database, including 16,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2624R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2709 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13680 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -1.22
• Publications: 15 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-38502916-C-T is Benign according to our data. Variant chr19-38502916-C-T is described in ClinVar as Benign. ClinVar VariationId is 93295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 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.7872C>T	p.Arg2624Arg	synonymous	Exon 49 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.7872C>T	p.Arg2624Arg	synonymous	Exon 49 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.7872C>T	p.Arg2624Arg	synonymous	Exon 49 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.7872C>T	p.Arg2624Arg	synonymous	Exon 49 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.7872C>T		non_coding_transcript_exon	Exon 49 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25736 AN: 151788 Hom.: 2695 Cov.: 31

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0575

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.149 AC: 37256 AN: 249646 AF XY: 0.144

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.0905

Gnomad EAS exome AF: 0.0459

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.130 AC: 189622 AN: 1459480 Hom.: 13680 Cov.: 40 AF XY: 0.130 AC XY: 94368 AN XY: 726146

African (AFR) AF: 0.285 AC: 9531 AN: 33472

American (AMR) AF: 0.251 AC: 11244 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0938 AC: 2451 AN: 26136

East Asian (EAS) AF: 0.0629 AC: 2498 AN: 39698

South Asian (SAS) AF: 0.160 AC: 13771 AN: 86252

European-Finnish (FIN) AF: 0.143 AC: 7328 AN: 51106

Middle Eastern (MID) AF: 0.112 AC: 646 AN: 5768

European-Non Finnish (NFE) AF: 0.120 AC: 133972 AN: 1111958

Other (OTH) AF: 0.135 AC: 8181 AN: 60378

GnomAD4 genome AF: 0.170 AC: 25789 AN: 151906 Hom.: 2709 Cov.: 31 AF XY: 0.171 AC XY: 12683 AN XY: 74254

African (AFR) AF: 0.283 AC: 11717 AN: 41352

American (AMR) AF: 0.191 AC: 2910 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3472

East Asian (EAS) AF: 0.0574 AC: 297 AN: 5172

South Asian (SAS) AF: 0.162 AC: 777 AN: 4802

European-Finnish (FIN) AF: 0.146 AC: 1548 AN: 10590

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7795 AN: 67944

Other (OTH) AF: 0.166 AC: 349 AN: 2106

Alfa AF: 0.131 Hom.: 1226

Bravo AF: 0.179

Asia WGS AF: 0.145 AC: 504 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (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 (2)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		-1.2
Mutation Taster		=96/4	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: rs1469698; hg19: chr19-38993556; COSMIC: COSV62107803;