TXNRD2

protein-coding

thioredoxin reductase 2, the group of Selenoproteins

Gene summary

The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

MANE transcript

NM_006440.5

Inheritance

AR, AD

ClinVar variants

P:1U:419B:248

Top phenotype

Glucocorticoid deficiency 5

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr22:19,875,517-19,941,820

External References & Databases

Ensembl (ENSG00000184470)

Transcript & Mutation Effects

hg38 • Region Span ~66.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glucocorticoid deficiency 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0040502

Submitter: PanelApp Australia

dilated cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: Ambry Genetics

familial glucocorticoid deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008733

Submitter: Orphanet

glucocorticoid deficiency 5LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0040502

Submitter: Labcorp Genetics (formerly Invitae)

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Clinical Genomic Database (CGD)

Glucocorticoid deficiency 5AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Individuals have been described as having glucocorticoid deficiency, with poor cortisol response to ACTH stimulation, and required glucocorticoid replacement therapy

Refs: 24601690

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TXNRD2 variants in ClinVar

9 Conditions Cataloged

Primary dilated cardiomyopathyTotal: 610

Cardiovascular phenotypeTotal: 497

not providedTotal: 190

not specifiedTotal: 61

Glucocorticoid deficiency 5Total: 33

TXNRD2-related disorderTotal: 31

Tramadol responseTotal: 5

TXNRD2-associated CardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006440.5. 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			6 clinvar	204 clinvar	4 clinvar	214
missense			366 clinvar	37 clinvar	3 clinvar	406
nonsense		1 clinvar	8 clinvar			9
start loss			2 clinvar			2
frameshift			12 clinvar			12
splice donor/acceptor (+/-2bp)			25 clinvar			25
Total	0	1	419	241	7	668

Highest pathogenic variant AF is 0.000011632028

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006440.5	RefSeq	NP_006431.2	17	MANE Select
ENST00000400521.7	Ensembl	ENSP00000383365.1	17	MANE Select
NM_001282512.3	RefSeq	NP_001269441.1	12	Standard
NM_001352300.2	RefSeq	NP_001339229.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Selenocompound metabolism - Homo sapiens (human)
Hepatocellular carcinoma - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Selenium Micronutrient Network
Selenium Metabolism and Selenoproteins

Biological Process

response to oxygen radical
electron transport chain
cellular response to oxidative stress
cell redox homeostasis
cellular oxidant detoxification

Molecular Function

thioredoxin-disulfide reductase activity
protein binding
electron transfer activity
flavin adenine dinucleotide binding

Cellular Component

cytoplasm
mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000400521
Coding exons: 17
Length: 66302
Individuals with no LoFs: 124688
Homozygous LoFs: 0
Heterozygous LoFs: 215
Defined: 124903
p: 0.000861

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.636	296	328	0.901	0.0000219	3308
Missense (PolyPhen)		120	140.22	0.85579		1370
Synonymous	-0.601	146	137	1.07	0.00000976	1088
Loss of Function	1.60	21	30.5	0.687	0.00000159	336

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00058	0.00058	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00054	0.00052	rare
South Asian	0.0039	0.0039	notable
Other	0.00083	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis (PubMed:24601690). Maintains thioredoxin in a reduced state. May play a role in redox-regulated cell signaling. {ECO:0000269|PubMed:24601690}.;

Recessive Scores

pRec: 0.337

Intolerance Scores

LoFtool: 0.597
RVIS EVS: 0.63
RVIS percentile EVS: 83.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.995

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High