NECAP1

Chr 12

NECAP endocytosis associated 1

Also known as: DEE21, EIEE21

NCBI Gene: 25977 ENSG00000089818 UniProt: Q8NC96

The encoded protein localizes to clathrin-coated vesicles and binds adapter protein complexes to facilitate endocytosis. Loss-of-function mutations cause developmental and epileptic encephalopathy 21, inherited in an autosomal recessive pattern. The pathogenic mechanism involves disrupted endocytosis due to impaired clathrin-coated vesicle function.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein containing two characteristic WXXF motifs. The encoded protein localizes to clathrin-coated vesicles, where it binds components of the adapter protein complexes and aids in endocytosis. Loss of function of this gene results in early infantile epileptic encephalopathy-21. There is a pseudogene for this gene on chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ResearchGenerating clinical summary…

LOEUF 0.65

Clinical Summary— NECAP1

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 109 VUS of 223 total submissions

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.126

Z-score 2.48

OE 0.29 (0.14–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.40Z-score

OE missense 0.69 (0.59–0.81)

110 obs / 160.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.14–0.65)

0≤0.351.4

Missense OE?0.69 (0.59–0.81)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 4 / 14.0Missense obs/exp: 110 / 160.0Syn Z: 1.08

ClinVar Variant Classifications

223 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS109

Likely Benign98

Benign5

Conflicting1

Pathogenic

Likely Pathogenic

109

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	0	0	3
Likely Pathogenic	2	0	0	0	2
VUS	0	99	8	2	109
Likely Benign	0	1	52	45	98
Benign	0	0	5	0	5
Conflicting	—				1
Total	5	100	65	47	218

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 53) ClinVar copy-number / structural variants overlap NECAP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →