rs539194350

Variant names:

• chr19-38565290-G-A
• rs539194350
• NM_000540.3:c.12956G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38565290-G-A
• chr19-38565290-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000540.3(RYR1):​c.12956G>A​(p.Arg4319Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000778 in 1,022,488 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4319P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 0.802
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020024508).
• BP6: Variant 19-38565290-G-A is Benign according to our data. Variant chr19-38565290-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 199217.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00277 (407/146902) while in subpopulation AFR AF = 0.0091 (373/41008). AF 95% confidence interval is 0.00833. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.12956G>A	p.Arg4319Gln	missense	Exon 91 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.12941G>A	p.Arg4314Gln	missense	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.12956G>A	p.Arg4319Gln	missense	Exon 91 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.12941G>A	p.Arg4314Gln	missense	Exon 90 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*3666G>A		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 406 AN: 146796 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000813

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000197

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.00 AC: 0 AN: 52 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000443 AC: 388 AN: 875586 Hom.: 2 Cov.: 30 AF XY: 0.000468 AC XY: 191 AN XY: 408126

African (AFR) AF: 0.00959 AC: 160 AN: 16692

American (AMR) AF: 0.000407 AC: 1 AN: 2456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6248

East Asian (EAS) AF: 0.000171 AC: 1 AN: 5862

South Asian (SAS) AF: 0.000960 AC: 17 AN: 17712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5170

Middle Eastern (MID) AF: 0.00220 AC: 4 AN: 1820

European-Non Finnish (NFE) AF: 0.000224 AC: 177 AN: 789750

Other (OTH) AF: 0.000937 AC: 28 AN: 29876

GnomAD4 genome AF: 0.00277 AC: 407 AN: 146902 Hom.: 1 Cov.: 32 AF XY: 0.00284 AC XY: 203 AN XY: 71520

African (AFR) AF: 0.00910 AC: 373 AN: 41008

American (AMR) AF: 0.000812 AC: 12 AN: 14786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5122

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000197 AC: 13 AN: 65960

Other (OTH) AF: 0.00196 AC: 4 AN: 2046

Alfa AF: 0.00208 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	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 specified (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.017	D
MutationAssessor	Benign	1.4	L
PhyloP100		0.80
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.32
Sift	Benign	0.10	T
Polyphen		0.71	P
Vest4		0.12
MutPred		0.25		Loss of methylation at R4314 (P = 0.1002)
MVP		0.96
MPC		0.66
ClinPred		0.50	D
GERP RS		2.7
PromoterAI		-0.022	Neutral
Varity_R		0.12
gMVP		0.27
Mutation Taster		=60/40	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: rs539194350; hg19: chr19-39055930;