SZT2

Chr 1

SZT2 subunit of KICSTOR complex

Also known as: C1orf84, DEE18, EIEE18, KIAA0467, KICS1, SZT2A, SZT2B

NCBI Gene: 23334 ENSG00000198198 UniProt: Q5T011

The protein is localized to peroxisomes and lysosomes and functions in resistance to oxidative stress by increasing superoxide dismutase activity. Biallelic mutations cause developmental and epileptic encephalopathy 18, an autosomal recessive disorder characterized by seizures and developmental delay. The pathogenic mechanism involves impaired oxidative stress resistance, which contributes to increased seizure susceptibility and epileptogenesis.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis. [provided by RefSeq, Jun 2011]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 18

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · genetic developmental and epileptic encephalopathy · AR · ClinGen 2021
Definitive · developmental and epileptic encephalopathy, 18 · AR · Illumina
Supportive · undetermined early-onset epileptic encephalopathy · AD · Orphanet

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.41

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — SZT2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.000

Z-score 8.52

OE 0.33 (0.27–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.60Z-score

OE missense 0.84 (0.80–0.87)

1666 obs / 1992.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.33 (0.27–0.41)

0≤0.351.4

Missense OE?0.84 (0.80–0.87)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 61 / 186.6Missense obs/exp: 1666 / 1992.2Syn Z: 0.23

Background carrier burden — how many people carry a rare variant somewhere in SZT2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 16

4,124 rare PASS variants

Rare truncating (LoF)

1 in 480

488 rare PASS variants

Rare synonymous (reference)

1 in 23

1,815 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SZT2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 23	1 in 560
South Asian	~43k	1 in 16	1 in 350
Remaining (unassigned)	~30k	1 in 15	1 in 290
European (Finnish)	~27k	1 in 40	1 in 1,200
Admixed American	~22k	1 in 16	1 in 600
African / African American	~21k	1 in 13	1 in 490
East Asian	~20k	1 in 17	1 in 360
Ashkenazi Jewish	~13k	1 in 49	1 in 1,000
Middle Eastern	~2,884	1 in 14	1 in 320

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 70 of 72 coding exons well covered in gnomAD exomes; exons 1, 41 marginal. Genomes: 71 of 72 (exon 14 below).? see exons ↓