rs75181912

Variant names:

• chr19-38494461-C-T
• rs75181912
• NM_000540.3:c.6384C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38494461-C-T
• chr19-38494461-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000540.3(RYR1):​c.6384C>T​(p.Tyr2128Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,612,800 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (15 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.24
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-38494461-C-T is Benign according to our data. Variant chr19-38494461-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00567 (864/152344) while in subpopulation AFR AF = 0.0159 (659/41574). AF 95% confidence interval is 0.0148. There are 3 homozygotes in GnomAd4. There are 408 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.6384C>T	p.Tyr2128Tyr	synonymous	Exon 39 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.6384C>T	p.Tyr2128Tyr	synonymous	Exon 39 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.6384C>T	p.Tyr2128Tyr	synonymous	Exon 39 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.6384C>T	p.Tyr2128Tyr	synonymous	Exon 39 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.6384C>T		non_coding_transcript_exon	Exon 39 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 855 AN: 152226 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00286 AC: 715 AN: 250226 AF XY: 0.00275

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00558

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.000839

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00222 AC: 3246 AN: 1460456 Hom.: 15 Cov.: 32 AF XY: 0.00220 AC XY: 1595 AN XY: 726568

African (AFR) AF: 0.0185 AC: 618 AN: 33450

American (AMR) AF: 0.00179 AC: 80 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 168 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00224 AC: 193 AN: 86198

European-Finnish (FIN) AF: 0.00117 AC: 62 AN: 53086

Middle Eastern (MID) AF: 0.00711 AC: 35 AN: 4922

European-Non Finnish (NFE) AF: 0.00171 AC: 1899 AN: 1111990

Other (OTH) AF: 0.00317 AC: 191 AN: 60282

GnomAD4 genome AF: 0.00567 AC: 864 AN: 152344 Hom.: 3 Cov.: 31 AF XY: 0.00548 AC XY: 408 AN XY: 74496

African (AFR) AF: 0.0159 AC: 659 AN: 41574

American (AMR) AF: 0.00222 AC: 34 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00103 AC: 11 AN: 10630

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00181 AC: 123 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00482 Hom.: 2

Bravo AF: 0.00624

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (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	-0.43
CADD	Benign	0.33
DANN	Benign	0.94
PhyloP100		-1.2
Mutation Taster		=92/8	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: rs75181912; hg19: chr19-38985101;