SEZ6L2

Chr 16

seizure related 6 homolog like 2

Also known as: BSRPA, PSK-1

NCBI Gene: 26470 ENSG00000174938 UniProt: Q6UXD5

The protein contributes to specialized endoplasmic reticulum functions in neurons and is localized on the cell surface. Mutations in this gene cause neurodevelopmental disorders with autism spectrum features, with the gene located in the chromosome 16p11.2 region associated with autism spectrum disorders. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.42), suggesting intolerance to complete protein loss.

ResearchSummary from RefSeq, UniProt

This gene encodes a seizure-related protein that is localized on the cell surface. The gene is located in a region of chromosome 16p11.2 that is thought to contain candidate genes for autism spectrum disorders (ASD), though there is no evidence directly implicating this gene in ASD. Increased expression of this gene has been found in lung cancers, and the protein is therefore considered to be a novel prognostic marker for lung cancer. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.42

Clinical Summary— SEZ6L2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

111 VUS of 158 total submissions

Explore recent and relevant literature in Research Assistant →

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?

0.42LOEUF

pLI 0.117

Z-score 4.42

OE 0.25 (0.15–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.75Z-score

OE missense 0.79 (0.73–0.86)

452 obs / 569.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.15–0.42)

0≤0.351.4

Missense OE?0.79 (0.73–0.86)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 10 / 40.3Missense obs/exp: 452 / 569.9Syn Z: 0.24

This gene — mechanism propensity

0.6647th %ile

GOF

0.77top 25%

LOF

0.3355th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

158 submitted variants in ClinVar

ClinVar

Classification Summary

VUS111

Likely Benign15

Benign9

111

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	111	0	111
Likely Benign	6	9	15
Benign	2	7	9
Total	119	16	135

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

282 pathogenic / likely-pathogenic (of 302) ClinVar copy-number / structural variants overlap SEZ6L2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →