SELENON

protein-coding

selenoprotein N, the group of Selenoproteins|EF-hand domain containing

Gene summary

This gene encodes a glycoprotein that is localized in the endoplasmic reticulum. It plays an important role in cell protection against oxidative stress, and in the regulation of redox-related calcium homeostasis. Mutations in this gene are associated with early onset muscle disorders, referred to as SEPN1-related myopathy. SEPN1-related myopathy consists of 4 autosomal recessive disorders, originally thought to be separate entities: rigid spine muscular dystrophy (RSMD1), the classical form of multiminicore disease, desmin related myopathy with Mallory-body like inclusions, and congenital fiber-type disproportion (CFTD). This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. A second stop-codon redefinition element (SRE) adjacent to the UGA codon has been identified in this gene (PMID:15791204). SRE is a phylogenetically conserved stem-loop structure that stimulates readthrough at the UGA codon, and augments the Sec insertion efficiency by SECIS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2016]

Previous symbols:

RSMD1
MDRS1
SEPN1

MANE transcript

N/A

Inheritance

AR, AD

ClinVar variants

P:86U:208B:121

Top phenotype

Congenital myopathy 3 with rigid spine; Myopathy, congenital, with fiber-type disproportion

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr1:25,800,193-25,818,221

External References & Databases

Ensembl (ENSG00000162430)

Transcript & Mutation Effects

hg38 • Region Span ~18.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

rigid spine muscular dystrophy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011271

Submitter: PanelApp Australia

congenital myopathy 3 with rigid spineDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100100

Submitter: ClinGen

SEPN1 (SELENON) was reported in relation to autosomal recessive SELENON-related myopathy in 2002 (Ferreiro et al., PMID: 12192640). At least 16 unique variants (missense, nonsense, splicing, and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 18 probands in 3 publications (PMID: 12192640, 16779558, 21670436). The mechanism of disease is homozygous loss of function. This gene-disease association is supported by animal models. In summary, SEPN1 (SELENON) is definitively associated with autosomal recessive SELENON-related myopathy.

congenital myopathy 4A, autosomal dominantSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800341

Submitter: Labcorp Genetics (formerly Invitae)

congenital fiber-type disproportion myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009711

Submitter: Orphanet

rigid spine syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019951

Submitter: Orphanet

rigid spine muscular dystrophy 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011271

Submitter: G2P

rigid spine muscular dystrophy 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011271

Submitter: Ambry Genetics

desmin-related myopathy with Mallory body-like inclusionsSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019398

Submitter: Orphanet

Clinical Genomic Database (CGD)

Congenital myopathy 3 with rigid spine; Myopathy, congenital, with fiber-type disproportionAR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Cardiac involvement has been described in some individuals

Refs: 7224095; 11528383; 12192640; 15122708; 16365872; 20301436; 20301467; 21670436

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SELENON variants in ClinVar

9 Conditions Cataloged

Eichsfeld type congenital muscular dystrophyTotal: 41

not providedTotal: 12

Eichsfeld type congenital muscular dystrophy;Congenital myopathy with fiber type disproportionTotal: 1

Congenital myopathy with fiber type disproportionTotal: 1

SELENON-related myopathyTotal: 1

SELENON-related disorderTotal: 1

Congenital myopathy 4A, autosomal dominantTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript . Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	105 clinvar	4 clinvar	112
missense		11 clinvar	198 clinvar	7 clinvar	5 clinvar	221
nonsense	10 clinvar	9 clinvar	1 clinvar			20
start loss	6 clinvar	4 clinvar				10
frameshift	23 clinvar	8 clinvar	3 clinvar			34
splice donor/acceptor (+/-2bp)	4 clinvar	11 clinvar	3 clinvar			18
Total	43	43	208	112	9	415

Highest pathogenic variant AF is 0.000118239

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
ENST00000361547.7	Ensembl	ENSP00000355141.2	13	MANE Select
NM_020451.3	RefSeq	NP_065184.2	13	Standard
NM_206926.2	RefSeq	NP_996809.1	12	Standard
ENST00000354177.9	Ensembl	ENSP00000346109.5	12	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
selenon	Danio rerio	Structure: slow muscle cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

selenon

Danio rerio

Structure: slow muscle cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Selenium Micronutrient Network
Selenium Metabolism and Selenoproteins

Biological Process

respiratory system process
mitochondrion organization
skeletal muscle satellite cell differentiation
skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration
positive regulation of skeletal muscle cell proliferation

Molecular Function

calcium ion binding
protein binding
oxidoreductase activity

Cellular Component

endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361547
Coding exons: 13
Length: 18047
Individuals with no LoFs: 124739
Homozygous LoFs: 0
Heterozygous LoFs: 93
Defined: 124832
p: 0.000373

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.424	275	296	0.931	0.0000194	3803
Missense (PolyPhen)		77	83.602	0.92103		957
Synonymous	-1.37	148	128	1.15	0.00000948	1196
Loss of Function	1.49	18	26.2	0.686	0.00000143	309

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00019	rare
Latino/Admixed American	0.00030	0.00029	rare
Ashkenazi Jewish	0.0014	0.0014	notable
East Asian	0.00031	0.00028	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00036	0.00035	rare
South Asian	0.00034	0.00033	rare
Other	0.00099	0.00099	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 2: Plays an important role in cell protection against oxidative stress and in the regulation of redox-related calcium homeostasis. Regulates the calcium level of the ER by protecting the calcium pump ATP2A2 against the oxidoreductase ERO1A-mediated oxidative damage. Within the ER, ERO1A activity increases the concentration of H(2)O(2), which attacks the luminal thiols in ATP2A2 and thus leads to cysteinyl sulfenic acid formation (-SOH) and SEPN1 reduces the SOH back to free thiol (- SH), thus restoring ATP2A2 activity (PubMed:25452428). Acts as a modulator of ryanodine receptor (RyR) activity: protects RyR from oxidation due to increased oxidative stress, or directly controls the RyR redox state, regulating the RyR-mediated calcium mobilization required for normal muscle development and differentiation (PubMed:19557870, PubMed:18713863). {ECO:0000269|PubMed:18713863, ECO:0000269|PubMed:19557870, ECO:0000269|PubMed:25452428}.;
Disease: DISEASE: Rigid spine muscular dystrophy 1 (RSMD1) [MIM:602771]: A neuromuscular disorder characterized by poor axial muscle strength, scoliosis and neck weakness, and a variable degree of spinal rigidity. Early ventilatory insufficiency can lead to death by respiratory failure. {ECO:0000269|PubMed:11528383, ECO:0000269|PubMed:12192640, ECO:0000269|PubMed:15122708, ECO:0000269|PubMed:15668457, ECO:0000269|PubMed:18713863, ECO:0000269|PubMed:19067361}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, congenital, with fiber-type disproportion (CFTD) [MIM:255310]: A genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. {ECO:0000269|PubMed:16365872}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.202

Intolerance Scores

RVIS EVS: 0.62
RVIS percentile EVS: 83.42

Essentials

Essential (gene trap): N