NECAB2

Summary

NECAB2 (N-terminal EF-hand calcium binding protein 2, HGNC:23746) is a protein-coding gene on chromosome 16q23.3, encoding N-terminal EF-hand calcium-binding protein 2 (Q7Z6G3). May act as a signaling scaffold protein that senses intracellular calcium.

The protein encoded by this gene is a neuronal calcium-binding protein that binds to and modulates the function of at least two receptors, adenosine A(2A) receptor and metabotropic glutamate receptor type 5.

Source: NCBI Gene 54550 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 200 total
• MANE Select transcript: NM_019065

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23746
Approved symbol	NECAB2
Name	N-terminal EF-hand calcium binding protein 2
Location	16q23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000103154
Ensembl biotype	protein_coding
OMIM	618130
Entrez	54550

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000305202, ENST00000564166, ENST00000565691, ENST00000566836, ENST00000567703, ENST00000681513, ENST00000933975, ENST00000933976, ENST00000933977

RefSeq mRNA: 3 — MANE Select: NM_019065 NM_001329748, NM_001329749, NM_019065

CCDS: CCDS10940, CCDS82019

Canonical transcript exons

ENST00000305202 — 13 exons

Exon	Start	End
ENSE00000695197	83990494	83990630
ENSE00000695255	84000724	84000801
ENSE00000695266	84001825	84001916
ENSE00001121073	83972151	83972175
ENSE00001174933	84002318	84002776
ENSE00001282367	83998205	83998317
ENSE00001290448	83981030	83981127
ENSE00001298998	83968244	83968849
ENSE00001334573	83980839	83980864
ENSE00003590696	83994609	83994688
ENSE00003600478	83978444	83978552
ENSE00003635749	83994302	83994420
ENSE00003642385	83997216	83997269

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 97.92.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3896 / max 197.9120, expressed in 325 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155277	2.2442	314
155276	0.1052	60
155278	0.0401	20

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	97.92	gold quality
caudate nucleus	UBERON:0001873	97.52	gold quality
amygdala	UBERON:0001876	96.84	gold quality
putamen	UBERON:0001874	96.35	gold quality
cingulate cortex	UBERON:0003027	95.98	gold quality
anterior cingulate cortex	UBERON:0009835	95.89	gold quality
right frontal lobe	UBERON:0002810	94.36	gold quality
temporal lobe	UBERON:0001871	93.65	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.36	gold quality
hypothalamus	UBERON:0001898	93.24	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.77	gold quality
prefrontal cortex	UBERON:0000451	92.24	gold quality
telencephalon	UBERON:0001893	91.63	gold quality
forebrain	UBERON:0001890	91.09	gold quality
frontal cortex	UBERON:0001870	90.83	gold quality
neocortex	UBERON:0001950	90.69	gold quality
entorhinal cortex	UBERON:0002728	90.48	gold quality
cerebral cortex	UBERON:0000956	90.25	gold quality
orbitofrontal cortex	UBERON:0004167	89.78	silver quality
type B pancreatic cell	CL:0000169	88.41	gold quality
cranial nerve II	UBERON:0000941	88.31	gold quality
Ammon’s horn	UBERON:0001954	88.17	gold quality
right lobe of liver	UBERON:0001114	87.81	gold quality
brain	UBERON:0000955	87.38	gold quality
central nervous system	UBERON:0001017	87.14	gold quality
olfactory bulb	UBERON:0002264	87.11	gold quality
superior frontal gyrus	UBERON:0002661	86.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.41	gold quality
pituitary gland	UBERON:0000007	85.01	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.54	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX6

miRNA regulators (miRDB)

22 targeting NECAB2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-6831-5P	98.26	67.20	990
HSA-MIR-3927-3P	97.68	66.76	892
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-7847-3P	96.63	64.58	952
HSA-MIR-6738-5P	96.33	63.61	815
HSA-MIR-1914-3P	95.07	63.37	762
HSA-MIR-3130-3P	94.98	66.97	574
HSA-MIR-1204	89.50	65.56	109

Literature-anchored findings (GeneRIF, showing 3)

• NECAB2 by its physical interaction with mGlu(5b) receptor modulates receptor function (PMID:19694902)
• Study suggests that the phenotypic segregation of Neuronal calcium-binding protein 1 and -2 (NECAB1 and -2) to respective excitatory and inhibitory spinal systems can underpin functional modalities in determining the fidelity of synaptic neurotransmission and neuronal responsiveness, and might bear translational relevance to humans. (PMID:26843217)
• NECAB2 is an endosomal protein important for striatal function. (PMID:37722569)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	necab2	ENSDARG00000056745
mus_musculus	Necab2	ENSMUSG00000031837
rattus_norvegicus	Necab2	ENSRNOG00000015084

Paralogs (2): NECAB1 (ENSG00000123119), NECAB3 (ENSG00000125967)

Protein

Protein identifiers

N-terminal EF-hand calcium-binding protein 2 — Q7Z6G3 (reviewed: Q7Z6G3)

Alternative names: Neuronal calcium-binding protein 2, Synaptotagmin-interacting protein 2

All UniProt accessions (3): Q7Z6G3, H3BPH6, H3BQC7

UniProt curated annotations — full annotation on UniProt →

Function. May act as a signaling scaffold protein that senses intracellular calcium. Can modulate ligand-induced internalization of ADORA2A and coupling efficiency of mGluR5/GRM5; for both receptors may regulate signaling activity such as promoting MAPK1/3 (ERK1/2) activation.

Subunit / interactions. Interacts (calcium-dependent) with ADORA2A and GRM5.

Subcellular location. Cytoplasm. Cell projection. Dendrite. Axon. Cell membrane.

Tissue specificity. Expressed in brain. Expressed in the spinal dorsal horn with especially strong expression in lamina IIi; found in excitory synaptic boutons and in ependymal cells (at protein level).

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z6G3-1	1	yes
Q7Z6G3-2	2

RefSeq proteins (3): NP_001316677, NP_001316678, NP_061938* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR007138	ABM_dom	Domain
IPR011008	Dimeric_a/b-barrel	Homologous_superfamily
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR039862	NECAB1/2/3	Family

Pfam: PF03992, PF13499

UniProt features (22 total): binding site 10, sequence variant 4, domain 3, modified residue 2, chain 1, splice variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z6G3-F1	74.40	0.41

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (10): 107; 109; 111; 113; 118; 73; 75; 77; 79; 84

Post-translational modifications (2): 10, 42

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): GOBP_G_PROTEIN_COUPLED_RECEPTOR_INTERNALIZATION, GOBP_G_PROTEIN_COUPLED_PURINERGIC_RECEPTOR_SIGNALING_PATHWAY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_GLYCOPROTEIN_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_RECEPTOR_INTERNALIZATION, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS

GO Biological Process (6): regulation of amyloid precursor protein biosynthetic process (GO:0042984), positive regulation of adenosine receptor signaling pathway (GO:0060168), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of glutamate receptor signaling pathway (GO:1900451), negative regulation of G protein-coupled receptor internalization (GO:1904021), positive regulation of protein localization to membrane (GO:1905477)

GO Molecular Function (6): calcium ion binding (GO:0005509), A2A adenosine receptor binding (GO:0031687), type 5 metabotropic glutamate receptor binding (GO:0031802), identical protein binding (GO:0042802), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): cytoplasm (GO:0005737), plasma membrane (GO:0005886), axon (GO:0030424), dendrite (GO:0030425), presynapse (GO:0098793), postsynapse (GO:0098794), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
neuron projection	2
synapse	2
regulation of glycoprotein biosynthetic process	1
amyloid precursor protein biosynthetic process	1
G protein-coupled adenosine receptor signaling pathway	1
positive regulation of G protein-coupled receptor signaling pathway	1
regulation of adenosine receptor signaling pathway	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
glutamate receptor signaling pathway	1
positive regulation of signal transduction	1
regulation of glutamate receptor signaling pathway	1
G protein-coupled receptor internalization	1
negative regulation of receptor internalization	1
regulation of G protein-coupled receptor internalization	1
positive regulation of cellular process	1
protein localization to membrane	1
positive regulation of protein localization	1
regulation of protein localization to membrane	1
metal ion binding	1
adenosine receptor binding	1
G protein-coupled glutamate receptor binding	1
protein binding	1
binding	1
cation binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
dendritic tree	1

Protein interactions and networks

STRING

1623 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NECAB2	SLC38A8	A6NNN8	536
NECAB2	ADORA2A	P29274	513
NECAB2	TAFA1	Q7Z5A9	506
NECAB2	CALB1	P05937	482
NECAB2	PCP4	P48539	459
NECAB2	TAC1	P20366	438
NECAB2	CBLN4	Q9NTU7	437
NECAB2	SLC17A7	Q9P2U7	436
NECAB2	RELN	P78509	431
NECAB2	GAD1	Q99259	423
NECAB2	DRD2	P14416	415
NECAB2	GAD2	Q05329	415
NECAB2	CYTH2	Q99418	403
NECAB2	PCDH8	O95206	400
NECAB2	LMO7	Q8WWI1	398

IntAct

37 interactions, top by confidence:

A	B	Type	Score
ADORA2A	NECAB2	psi-mi:“MI:0915”(physical association)	0.710
NECAB2	ADORA2A	psi-mi:“MI:0407”(direct interaction)	0.710
ADORA2A	NECAB2	psi-mi:“MI:0407”(direct interaction)	0.710
NECAB2	ADORA2A	psi-mi:“MI:0403”(colocalization)	0.710
NECAB2	LNX1	psi-mi:“MI:0915”(physical association)	0.550
NECAB1	CCDC6	psi-mi:“MI:0914”(association)	0.530
NECAB2	GRM5	psi-mi:“MI:0915”(physical association)	0.400
GRM5	NECAB2	psi-mi:“MI:0915”(physical association)	0.400
NECAB2		psi-mi:“MI:0915”(physical association)	0.370
NECAB2	gB	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	EHHADH	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	KPNA2	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	SH2D4A	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	NEK6	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	FMR1	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	FXR1	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	FXR2	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	SMARCA2	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	TSC1	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	ADAMTSL2	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	POLR2C	psi-mi:“MI:0915”(physical association)	0.370
ISCU	NECAB2	psi-mi:“MI:0915”(physical association)	0.370
USHBP1	NECAB2	psi-mi:“MI:0915”(physical association)	0.370
NECAB2	CCDC121	psi-mi:“MI:0915”(physical association)	0.370
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350

BioGRID (161): NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid), NECAB2 (Two-hybrid)

ESM2 similar proteins: A1L3C1, A2AWP8, A2RRU4, A6QM06, A6QNS9, E1BBQ2, F1LQY6, G3V9M2, O43189, O94827, P29372, P29590, P41155, P97260, Q01113, Q02833, Q04841, Q0P5I0, Q12770, Q13387, Q13505, Q29RM4, Q32L49, Q3V1H9, Q5MNU5, Q5R5M3, Q66T02, Q69Z89, Q6GQT6, Q6IPT2, Q6RFZ7, Q6ZN54, Q70EL4, Q7Z6G3, Q8BQB4, Q8C4U2, Q8N1F8, Q8N554, Q8WWW0, Q8WXF8

Diamond homologs: A2VDW6, F1LQY6, Q5R467, Q7Z6G3, Q8BG18, Q8N987, Q91ZP9, Q96P71, Q9D6J4, Q9ESB5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

200 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	176
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2546 predictions. Top by Δscore:

Variant	Effect	Δscore
16:83968846:GGAC:G	donor_gain	1.0000
16:83968847:GACG:G	donor_gain	1.0000
16:83968850:G:GG	donor_gain	1.0000
16:83978441:CAGA:C	acceptor_loss	1.0000
16:83978442:A:AG	acceptor_gain	1.0000
16:83978442:A:T	acceptor_loss	1.0000
16:83978442:AGAT:A	acceptor_gain	1.0000
16:83978443:G:GA	acceptor_gain	1.0000
16:83978443:GA:G	acceptor_gain	1.0000
16:83978443:GAT:G	acceptor_gain	1.0000
16:83978443:GATG:G	acceptor_gain	1.0000
16:83978443:GATGA:G	acceptor_gain	1.0000
16:83978548:ACCAA:A	donor_gain	1.0000
16:83978549:CCAA:C	donor_gain	1.0000
16:83978551:AA:A	donor_gain	1.0000
16:83978552:AGTG:A	donor_loss	1.0000
16:83978553:G:GG	donor_gain	1.0000
16:83981024:CCCCA:C	acceptor_loss	1.0000
16:83981025:CCCAG:C	acceptor_loss	1.0000
16:83981026:CCAG:C	acceptor_loss	1.0000
16:83981027:CAG:C	acceptor_loss	1.0000
16:83981028:A:AG	acceptor_gain	1.0000
16:83981028:AGAT:A	acceptor_loss	1.0000
16:83981029:G:GA	acceptor_gain	1.0000
16:83981029:GA:G	acceptor_gain	1.0000
16:83981029:GAT:G	acceptor_gain	1.0000
16:83981029:GATT:G	acceptor_gain	1.0000
16:83981029:GATTA:G	acceptor_gain	1.0000
16:83981124:GAAG:G	donor_gain	1.0000
16:83981125:AAGG:A	donor_loss	1.0000

AlphaMissense

2528 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:83978471:T:C	F85S	0.999
16:83990537:T:C	F168S	0.999
16:83990543:T:C	L170P	0.999
16:83968848:A:T	D67V	0.998
16:83972160:C:A	R71S	0.998
16:83978456:T:A	L80Q	0.998
16:83978456:T:C	L80P	0.998
16:83978470:T:C	F85L	0.998
16:83978472:C:A	F85L	0.998
16:83978472:C:G	F85L	0.998
16:83978482:T:C	F89L	0.998
16:83978484:T:A	F89L	0.998
16:83978484:T:G	F89L	0.998
16:83978522:T:C	L102P	0.998
16:83978524:T:C	F103L	0.998
16:83978526:T:A	F103L	0.998
16:83978526:T:G	F103L	0.998
16:83980859:T:C	L119P	0.998
16:83981036:T:C	F123S	0.998
16:83981078:T:C	L137P	0.998
16:83981099:T:A	V144D	0.998
16:83990524:T:C	F164L	0.998
16:83990526:T:A	F164L	0.998
16:83990526:T:G	F164L	0.998
16:83990536:T:C	F168L	0.998
16:83990538:C:A	F168L	0.998
16:83990538:C:G	F168L	0.998
16:83990540:T:C	L169P	0.998
16:83990573:T:C	L180P	0.998
16:83972155:T:C	F69S	0.997

dbSNP variants (sampled 300 via entrez): RS1000036962 (16:83989596 C>G,T), RS1000050619 (16:83993513 C>A,T), RS1000142109 (16:83985450 T>A), RS1000159572 (16:83968860 G>A,C), RS1000164617 (16:83975568 G>A), RS1000180878 (16:83996496 C>T), RS1000238534 (16:83999834 A>C), RS1000298331 (16:83968085 G>T), RS1000366786 (16:83993971 C>T), RS1000444794 (16:83968638 G>A), RS1000488647 (16:83972727 C>T), RS1000494057 (16:83979559 G>A), RS1000601495 (16:83969277 C>G), RS1000715280 (16:83984445 G>A,T), RS1000747458 (16:83984842 C>G,T)

Disease associations

OMIM: gene MIM:618130 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002692_3	Body mass index (change over time)	9.000000e-06
GCST004097_3	Response to platinum-based neoadjuvant chemotherapy in cervical cancer	3.000000e-06
GCST005803_10	Corneal astigmatism	6.000000e-06
GCST007843_24	Rheumatoid arthritis	1.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005937	longitudinal BMI measurement
EFO:0007943	response to platinum-based neoadjuvant chemotherapy
EFO:1002040	Corneal astigmatism

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Valproic Acid	affects expression, increases methylation	2
aminomethylphosphonic acid (AMPA)	decreases expression	1
propionaldehyde	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
trichostatin A	decreases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Glyphosate	decreases expression	1
Aldehydes	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	increases expression	1
Rotenone	increases expression	1
Silicon Dioxide	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
2,4-Dichlorophenoxyacetic Acid	decreases expression	1
Cadmium Chloride	increases expression	1
Zinc Sulfate	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.