NECAP1

protein-coding

NECAP endocytosis associated 1

Gene summary

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]

MANE transcript

NM_015509.4

Inheritance

AR, AD

ClinVar variants

P:5U:108B:50

Top phenotype

Developmental and epileptic encephalopathy 21

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr12:8,076,939-8,097,881

External References & Databases

Ensembl (ENSG00000089818)

Transcript & Mutation Effects

hg38 • Region Span ~20.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 21MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014360

Submitter: PanelApp Australia

genetic developmental and epileptic encephalopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

NECAP1 was first reported in relation to autosomal recessive developmental and epileptic encephalopathy in 2014 (Alazami et al., PMID 24399846). This condition is characterized by onset of seizures before 3 months of age, global developmental delay, and hypotonia. At least 3 variants (e.g. missense, splice, and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Summary of Case Level Data: 6.2 points. Variants in this gene have been reported in at least 5 probands in 6 publications (PMIDs: 24399846, 30202406, 30525121, 30626896, 32552793, 35638367). Notably, four of these publications report individuals from Saudi Arabia with the same p.R48* founder variant. The GCEP capped the curation weight provided by this variant at 6 points to avoid over-interpreting its importance (this includes 3 points for variant interpretation and 3 points for segregation). Variants in this gene segregated with disease in 5 additional affected family members. The mechanism for disease appears to be homozygous loss of function (PMID: 24399846, 30626896). This gene-disease association is also supported by biochemical function and protein interaction studies. NECAP1 has a role in Clathrin-mediated endocytosis, is essential to synaptic vesicle recycling, and which directly controls neuronal excitability (PMID: 35115907). While the biochemical role of NECAP1 is supportive of a role in seizures, it was not considered to be specific enough evidence to count towards clinical validity for the gene. The protein encoded by NECAP1 binds AP2 (PMID: 31430451) which is encoded by AP2M1 and is associated with seizures (PMID: 31104773). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy GCI on the meeting date January 17, 2023 (SOP Version 9).

developmental and epileptic encephalopathy, 21STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014360

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 21MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014360

Submitter: Ambry Genetics

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 21AR

Manifestation: Neurologic

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: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 24399846; 30525121; 30626896

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NECAP1 variants in ClinVar

5 Conditions Cataloged

Developmental and epileptic encephalopathy, 21Total: 191

Inborn genetic diseasesTotal: 25

not providedTotal: 24

not specifiedTotal: 9

NECAP1-related disorderTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015509.4. 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			2 clinvar	47 clinvar		49
missense			105 clinvar	3 clinvar		108
nonsense		1 clinvar				1
start loss						0
frameshift	2 clinvar	1 clinvar				3
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	3	2	108	50	0	163

Highest pathogenic variant AF is 0.0000030978513

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015509.4	RefSeq	NP_056324.2	8	MANE Select
ENST00000339754.11	Ensembl	ENSP00000341737.5	8	MANE Select
ENST00000450991.6	Ensembl	ENSP00000401963.2	4	Standard
ENST00000540083.1	Ensembl	ENSP00000439319.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Golgi Associated Vesicle Biogenesis
Clathrin derived vesicle budding
trans-Golgi Network Vesicle Budding
Vesicle-mediated transport
Membrane Trafficking

Biological Process

endocytosis
protein transport
membrane organization

Cellular Component

cytosol
plasma membrane
clathrin-coated pit
clathrin vesicle coat

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000339754
Coding exons: 8
Length: 15561
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125747
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.40	110	160	0.688	0.00000848	1779
Missense (PolyPhen)		27	48.315	0.55883		561
Synonymous	1.08	48	58.5	0.820	0.00000303	556
Loss of Function	2.48	4	14.0	0.285	6.78e-7	163

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000063	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in endocytosis. {ECO:0000250}.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 21 (EIEE21) [MIM:615833]: A severe disease characterized by intractable seizures, profound global developmental delay, and persistent severe axial hypotonia as well as appendicular hypertonia. {ECO:0000269|PubMed:24399846}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: -0.1
RVIS percentile EVS: 46.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.840

Gene Damage Prediction

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