19-38466364-C-T

Variant names:

• chr19-38466364-C-T
• rs143242075
• NM_000540.3:c.3144C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000540.3(RYR1):​c.3144C>T​(p.Tyr1048Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 1,571,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.43
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, 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), Genomics England PanelApp, Orphanet
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 19-38466364-C-T is Benign according to our data. Variant chr19-38466364-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 256489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.

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.3144C>T	p.Tyr1048Tyr	synonymous	Exon 24 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.3144C>T	p.Tyr1048Tyr	synonymous	Exon 24 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.3144C>T	p.Tyr1048Tyr	synonymous	Exon 24 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.3144C>T	p.Tyr1048Tyr	synonymous	Exon 24 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.3144C>T		non_coding_transcript_exon	Exon 24 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 7 AN: 175960 AF XY: 0.0000211

Gnomad AFR exome AF: 0.000385

Gnomad AMR exome AF: 0.0000370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000775

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000136

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000190 AC: 27 AN: 1419370 Hom.: 0 Cov.: 38 AF XY: 0.0000128 AC XY: 9 AN XY: 703028

African (AFR) AF: 0.000186 AC: 6 AN: 32322

American (AMR) AF: 0.0000778 AC: 3 AN: 38582

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25446

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37020

South Asian (SAS) AF: 0.0000246 AC: 2 AN: 81372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4524

European-Non Finnish (NFE) AF: 0.0000128 AC: 14 AN: 1093140

Other (OTH) AF: 0.00 AC: 0 AN: 58778

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.000121 AC: 5 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.046
DANN	Benign	0.47
PhyloP100		-1.4

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: rs143242075; hg19: chr19-38957004; COSMIC: COSV100614898;