chr19-38565651-C-T

Variant names:

• chr19-38565651-C-T
• rs113579185
• NM_000540.3:c.13317C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.13317C>T​(p.Ala4439Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,388,862 control chromosomes in the GnomAD database, including 1,462 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. A4439A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.042 (201 hom., cov: 31)
  • Exomes 𝑓: 0.043 (1261 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:14 O:1
• Conservation: PhyloP100: -2.00
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-38565651-C-T is Benign according to our data. Variant chr19-38565651-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0595 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.13317C>T	p.Ala4439Ala	synonymous	Exon 91 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.13302C>T	p.Ala4434Ala	synonymous	Exon 90 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.13317C>T	p.Ala4439Ala	synonymous	Exon 91 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.13302C>T	p.Ala4434Ala	synonymous	Exon 90 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*4027C>T		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6334 AN: 151964 Hom.: 201 Cov.: 31

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0401

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0499

GnomAD2 exomes AF: 0.0545 AC: 769 AN: 14112 AF XY: 0.0554

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.0439

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.0566

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0426 AC: 52680 AN: 1236784 Hom.: 1261 Cov.: 31 AF XY: 0.0428 AC XY: 25815 AN XY: 602802

African (AFR) AF: 0.0105 AC: 255 AN: 24218

American (AMR) AF: 0.0373 AC: 454 AN: 12156

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 1396 AN: 17418

East Asian (EAS) AF: 0.000213 AC: 6 AN: 28206

South Asian (SAS) AF: 0.0364 AC: 2044 AN: 56212

European-Finnish (FIN) AF: 0.110 AC: 3245 AN: 29608

Middle Eastern (MID) AF: 0.0664 AC: 234 AN: 3522

European-Non Finnish (NFE) AF: 0.0422 AC: 42768 AN: 1014318

Other (OTH) AF: 0.0446 AC: 2278 AN: 51126

GnomAD4 genome AF: 0.0416 AC: 6331 AN: 152078 Hom.: 201 Cov.: 31 AF XY: 0.0449 AC XY: 3336 AN XY: 74348

African (AFR) AF: 0.0113 AC: 471 AN: 41524

American (AMR) AF: 0.0399 AC: 610 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3470

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5142

South Asian (SAS) AF: 0.0347 AC: 167 AN: 4818

European-Finnish (FIN) AF: 0.116 AC: 1233 AN: 10594

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0504 AC: 3428 AN: 67950

Other (OTH) AF: 0.0489 AC: 103 AN: 2108

Alfa AF: 0.0277 Hom.: 15

Bravo AF: 0.0352

Asia WGS AF: 0.0170 AC: 61 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	1	2	not provided (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	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.29
DANN	Benign	0.96
PhyloP100		-2.0
PromoterAI		0.026	Neutral
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: rs113579185; hg19: chr19-39056291;