19-38565324-C-T

Variant names:

• chr19-38565324-C-T
• rs184450380
• NM_000540.3:c.12990C>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.12990C>T​(p.Thr4330Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,175,862 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T4330T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0079 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (14 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.05
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-38565324-C-T is Benign according to our data. Variant chr19-38565324-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00786 (1162/147874) while in subpopulation AFR AF = 0.0269 (1104/41026). AF 95% confidence interval is 0.0256. There are 19 homozygotes in GnomAd4. There are 550 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.12990C>T	p.Thr4330Thr	synonymous	Exon 91 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.12975C>T	p.Thr4325Thr	synonymous	Exon 90 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.12990C>T	p.Thr4330Thr	synonymous	Exon 91 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.12975C>T	p.Thr4325Thr	synonymous	Exon 90 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*3700C>T		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00776 AC: 1146 AN: 147768 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00296

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00539

GnomAD2 exomes AF: 0.00 AC: 0 AN: 82 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000796 AC: 818 AN: 1027988 Hom.: 14 Cov.: 30 AF XY: 0.000765 AC XY: 371 AN XY: 485032

African (AFR) AF: 0.0324 AC: 676 AN: 20848

American (AMR) AF: 0.00197 AC: 13 AN: 6600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11794

East Asian (EAS) AF: 0.00 AC: 0 AN: 21402

South Asian (SAS) AF: 0.000104 AC: 2 AN: 19150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18982

Middle Eastern (MID) AF: 0.00491 AC: 13 AN: 2646

European-Non Finnish (NFE) AF: 0.0000203 AC: 18 AN: 886982

Other (OTH) AF: 0.00243 AC: 96 AN: 39584

GnomAD4 genome AF: 0.00786 AC: 1162 AN: 147874 Hom.: 19 Cov.: 32 AF XY: 0.00763 AC XY: 550 AN XY: 72094

African (AFR) AF: 0.0269 AC: 1104 AN: 41026

American (AMR) AF: 0.00296 AC: 44 AN: 14880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8996

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66356

Other (OTH) AF: 0.00533 AC: 11 AN: 2062

Alfa AF: 0.000210 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Malignant hyperthermia, susceptibility to, 1 (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	-0.61
CADD	Benign	3.5
DANN	Benign	0.96
PhyloP100		-1.1
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	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: rs184450380; hg19: chr19-39055964;