NCALD

Summary

NCALD (neurocalcin delta, HGNC:7655) is a protein-coding gene on chromosome 8q22.3, encoding Neurocalcin-delta (P61601). May be involved in the calcium-dependent regulation of rhodopsin phosphorylation.

This gene encodes a member of the neuronal calcium sensor (NCS) family of calcium-binding proteins. The protein contains an N-terminal myristoylation signal and four EF-hand calcium binding loops. The protein is cytosolic at resting calcium levels; however, elevated intracellular calcium levels induce a conformational change that exposes the myristoyl group, resulting in protein association with membranes and partial co-localization with the perinuclear trans-golgi network. The protein is thought to be a regulator of G protein-coupled receptor signal transduction. Several alternatively spliced variants of this gene have been determined, all of which encode the same protein; additional variants may exist but their biological validity has not been determined.

Source: NCBI Gene 83988 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 22 total
• MANE Select transcript: NM_032041

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7655
Approved symbol	NCALD
Name	neurocalcin delta
Location	8q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000104490
Ensembl biotype	protein_coding
OMIM	606722
Entrez	83988

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 24 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000220931, ENST00000311028, ENST00000395923, ENST00000517531, ENST00000517639, ENST00000517822, ENST00000518166, ENST00000518661, ENST00000518727, ENST00000518952, ENST00000519098, ENST00000519508, ENST00000520346, ENST00000520425, ENST00000520690, ENST00000521371, ENST00000521599, ENST00000521957, ENST00000521964, ENST00000522078, ENST00000522206, ENST00000522252, ENST00000522448, ENST00000522754, ENST00000522951, ENST00000523645, ENST00000523923, ENST00000524101, ENST00000524137, ENST00000524209

RefSeq mRNA: 8 — MANE Select: NM_032041 NM_001040624, NM_001040625, NM_001040626, NM_001040627, NM_001040628, NM_001040629, NM_001040630, NM_032041

CCDS: CCDS6292

Canonical transcript exons

ENST00000220931 — 4 exons

Exon	Start	End
ENSE00001161961	101719252	101719648
ENSE00001772058	101692791	101692896
ENSE00002118231	101686542	101689406
ENSE00002119971	101790862	101790969

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 99.22.

FANTOM5 (CAGE): breadth broad, TPM avg 10.4987 / max 961.6922, expressed in 805 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94235	7.6271	610
94252	1.7778	474
94236	0.7360	230
94240	0.1601	30
94232	0.1109	47
94241	0.0564	18
205276	0.0216	5
94242	0.0089	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 10	UBERON:0013541	99.22	gold quality
frontal pole	UBERON:0002795	98.95	gold quality
prefrontal cortex	UBERON:0000451	97.43	gold quality
primary visual cortex	UBERON:0002436	97.24	gold quality
orbitofrontal cortex	UBERON:0004167	96.86	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.78	gold quality
frontal cortex	UBERON:0001870	96.63	gold quality
frontal lobe	UBERON:0016525	96.63	gold quality
occipital lobe	UBERON:0002021	96.58	gold quality
middle temporal gyrus	UBERON:0002771	96.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.52	gold quality
neocortex	UBERON:0001950	96.08	gold quality
right frontal lobe	UBERON:0002810	95.84	gold quality
cortical plate	UBERON:0005343	95.61	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.60	gold quality
superior frontal gyrus	UBERON:0002661	95.58	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.51	gold quality
cerebral cortex	UBERON:0000956	95.19	gold quality
cingulate cortex	UBERON:0003027	94.73	gold quality
anterior cingulate cortex	UBERON:0009835	94.71	gold quality
parietal lobe	UBERON:0001872	94.62	gold quality
postcentral gyrus	UBERON:0002581	94.42	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.39	gold quality
endothelial cell	CL:0000115	94.07	silver quality
lateral nuclear group of thalamus	UBERON:0002736	92.73	gold quality
right uterine tube	UBERON:0001302	92.43	gold quality
left ovary	UBERON:0002119	92.36	gold quality
temporal lobe	UBERON:0001871	92.22	gold quality
entorhinal cortex	UBERON:0002728	92.16	gold quality
Ammon’s horn	UBERON:0001954	92.03	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-6911	yes	730.60
E-MTAB-10287	yes	44.23
E-ANND-3	yes	14.12
E-CURD-114	yes	10.72
E-GEOD-93593	yes	4.74
E-MTAB-9067	yes	3.78
E-HCAD-5	no	2.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

145 targeting NCALD, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394

Literature-anchored findings (GeneRIF, showing 9)

• association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (PMID:17671797)
• Studies show that a fold recognition based model of the catalytic domain of ROS-GC1 was built, and neurocalcin delta docking simulations were carried out to define the three-dimensional features of the interacting domains of the two molecules. (PMID:18500817)
• It is presumed that NCALD is related to diabetic nephropathy by promoting epithelial mesenchymal transform. (PMID:23156397)
• Neurocalcin delta is a protective spinal muscular atrophy modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. (PMID:28132687)
• Coffee consumption is causally associated with an increased risk of osteoarthritis. SNPs in NCALD, POR, CYP1A1 and NRCAM were identified. (PMID:30076541)
• high expression of NCALD gene is a poor prognostic factor for cytogenetic normal acute myeloid leukemia. (PMID:31109331)
• NCALD affects drug resistance and prognosis by acting as a ceRNA of CX3CL1 in ovarian cancer. (PMID:32030795)
• Low expression of NCALD is associated with chemotherapy resistance and poor prognosis in epithelial ovarian cancer. (PMID:32228639)
• The author characterizes the biochemical properties of recombinant bovine neurocalcin delta, whose protein sequence is identical to the human ortholog (PMID:7852401)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncalda	ENSDARG00000070688
mus_musculus	Ncald	ENSMUSG00000051359
rattus_norvegicus	Ncald	ENSRNOG00000042978
drosophila_melanogaster	Nca	FBGN0013303

Paralogs (14): CLXN (ENSG00000034239), GUCA1A (ENSG00000048545), NCS1 (ENSG00000107130), RCVRN (ENSG00000109047), GUCA1B (ENSG00000112599), KCNIP3 (ENSG00000115041), HPCAL1 (ENSG00000115756), HPCAL4 (ENSG00000116983), KCNIP2 (ENSG00000120049), HPCA (ENSG00000121905), GUCA1C (ENSG00000138472), VSNL1 (ENSG00000163032), KCNIP1 (ENSG00000182132), KCNIP4 (ENSG00000185774)

Protein

Protein identifiers

Neurocalcin-delta — P61601 (reviewed: P61601)

All UniProt accessions (19): P61601, A0A1B0GXG3, B2RB70, E5RFL9, E5RGA9, E5RGZ0, E5RHC8, E5RHE8, E5RI78, E5RI95, E5RIA5, E5RIG4, E5RIX3, E5RIZ1, E5RJA1, E5RJF1, E5RJJ6, E5RJT1, E5RK89

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in the calcium-dependent regulation of rhodopsin phosphorylation. Binds three calcium ions.

Subunit / interactions. Interacts with GUCY2D.

Tissue specificity. Retina, cerebrum, cerebellum, brain stem, spinal cord, testis, ovary and small intestine.

Similarity. Belongs to the recoverin family.

RefSeq proteins (8): NP_001035714, NP_001035715, NP_001035716, NP_001035717, NP_001035718, NP_001035719, NP_001035720, NP_114430* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028846	Recoverin	Family

Pfam: PF00036, PF13499

UniProt features (24 total): binding site 15, domain 4, sequence conflict 2, initiator methionine 1, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61601-F1	86.88	0.65

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 (15): 84; 109; 111; 113; 115; 120; 157; 159; 161; 163; 168; 73 …

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-451308	Activation of Ca-permeable Kainate Receptor
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-451306	Ionotropic activity of kainate receptors
R-HSA-451326	Activation of kainate receptors upon glutamate binding

MSigDB gene sets: 248 (showing top): ATF_B, RRAGTTGT_UNKNOWN, REACTOME_IONOTROPIC_ACTIVITY_OF_KAINATE_RECEPTORS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, CREBP1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, MODULE_66, CAGCAGG_MIR370, ATF1_Q6, NF1_Q6_01

GO Biological Process (4): regulation of systemic arterial blood pressure (GO:0003073), regulation of signal transduction (GO:0009966), vesicle-mediated transport (GO:0016192), calcium-mediated signaling (GO:0019722)

GO Molecular Function (7): actin binding (GO:0003779), calcium ion binding (GO:0005509), tubulin binding (GO:0015631), clathrin binding (GO:0030276), alpha-tubulin binding (GO:0043014), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (2): cytosol (GO:0005829), clathrin coat of trans-Golgi network vesicle (GO:0030130)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Ionotropic activity of kainate receptors	1
Transmission across Chemical Synapses	1
Neuronal System	1
Activation of kainate receptors upon glutamate binding	1
Neurotransmitter receptors and postsynaptic signal transmission	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeletal protein binding	2
regulation of blood pressure	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
transport	1
cellular process	1
intracellular signaling cassette	1
metal ion binding	1
protein binding	1
tubulin binding	1
binding	1
cation binding	1
cytoplasm	1
cellular anatomical structure	1
Golgi apparatus	1
trans-Golgi network transport vesicle membrane	1
clathrin vesicle coat	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

137 interactions, top by confidence:

A	B	Type	Score
DTX2	NCALD	psi-mi:“MI:0915”(physical association)	0.800
NCALD	DTX2	psi-mi:“MI:0915”(physical association)	0.800
C1QTNF2	NCALD	psi-mi:“MI:0915”(physical association)	0.750
NCALD	C1QTNF2	psi-mi:“MI:0915”(physical association)	0.750
NCALD	SPRED1	psi-mi:“MI:0915”(physical association)	0.720
NDUFB5	NDUFB3	psi-mi:“MI:0914”(association)	0.640
VTCN1	NCALD	psi-mi:“MI:0915”(physical association)	0.590
HSPBAP1	NCALD	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (72): NCALD (Two-hybrid), DTX2 (Two-hybrid), C1QTNF2 (Two-hybrid), NCALD (Affinity Capture-MS), NCALD (Affinity Capture-MS), NCALD (Affinity Capture-MS), NCALD (Affinity Capture-MS), NCALD (Affinity Capture-MS), DTX2 (Two-hybrid), NCALD (Affinity Capture-Western), NCALD (Two-hybrid), NCALD (Two-hybrid), NCALD (Affinity Capture-MS), NCALD (Affinity Capture-MS), NCALD (Affinity Capture-MS)

ESM2 similar proteins: A9JTH1, B3DLU1, B3VSB7, B5FZ84, P29104, P29105, P35332, P36608, P37235, P37236, P42324, P42325, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762, P62763, P62764, P84074, P84075, P84076, Q06AT0, Q06AT1, Q09711, Q16982, Q28IM6, Q4PL64, Q4R4N4, Q4R5F7, Q5PQN0, Q5R632, Q5R6S5

Diamond homologs: A9JTH1, B3DLU1, B3VSB7, B5FZ84, O73761, O73762, O73763, O95843, P21457, P22728, P25296, P29104, P29105, P31227, P34057, P35243, P35332, P36608, P36609, P37235, P37236, P42322, P42324, P42325, P43080, P43081, P46065, P51177, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

4676 predictions. Top by Δscore:

Variant	Effect	Δscore
8:101719644:TTCAG:T	acceptor_gain	1.0000
8:101719646:CAG:C	acceptor_gain	1.0000
8:101779922:A:AC	donor_gain	1.0000
8:101779923:C:CC	donor_gain	1.0000
8:101915803:ACTT:A	donor_loss	1.0000
8:101915805:TTAC:T	donor_loss	1.0000
8:101915806:TACTT:T	donor_loss	1.0000
8:101915807:A:AC	donor_gain	1.0000
8:101915807:A:C	donor_loss	1.0000
8:101915808:C:CA	donor_gain	1.0000
8:101915808:CTTT:C	donor_gain	1.0000
8:102020231:ACTT:A	donor_loss	1.0000
8:102020232:CTTA:C	donor_loss	1.0000
8:102020234:TACCT:T	donor_loss	1.0000
8:102020236:C:A	donor_loss	1.0000
8:102124232:CTCA:C	donor_loss	1.0000
8:102124234:CA:C	donor_loss	1.0000
8:102124235:A:AC	donor_gain	1.0000
8:102124235:A:C	donor_loss	1.0000
8:102124235:ACCG:A	donor_gain	1.0000
8:102124236:C:CC	donor_gain	1.0000
8:102124236:CCG:C	donor_gain	1.0000
8:102124236:CCGC:C	donor_gain	1.0000
8:101689405:TCC:T	acceptor_loss	0.9900
8:101689407:C:A	acceptor_loss	0.9900
8:101689407:C:CC	acceptor_gain	0.9900
8:101689408:T:A	acceptor_loss	0.9900
8:101692790:CCGT:C	donor_gain	0.9900
8:101692893:TTGC:T	acceptor_gain	0.9900
8:101692894:TGC:T	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000130 (8:101944508 G>A), RS1000008228 (8:101940667 A>G), RS1000024989 (8:101805843 T>A), RS1000025054 (8:101846529 G>A), RS1000038500 (8:101933606 T>C), RS1000041093 (8:101976059 A>C,T), RS1000043469 (8:101815443 TAA>T,TAAA), RS1000056354 (8:101846880 G>A), RS1000069542 (8:102073477 A>G), RS1000071028 (8:101938347 C>T), RS1000073808 (8:102118252 A>G), RS1000079563 (8:101895938 C>G,T), RS1000083197 (8:101786965 G>T), RS1000088109 (8:101964174 T>A), RS1000116005 (8:101793921 C>G)

Disease associations

OMIM: gene MIM:606722 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000579_36	Cognitive performance	5.000000e-06
GCST001215_3	Coffee consumption	8.000000e-07
GCST002491_9	Age-related hearing impairment	8.000000e-06
GCST002588_6	Cerebral amyloid angiopathy	9.000000e-06
GCST002989_11	LDL peak particle diameter (total fat intake interaction)	5.000000e-06
GCST003253_13	Microalbuminuria	8.000000e-06
GCST004110_18	Gait speed in old age	2.000000e-06
GCST006628_49	Systolic blood pressure	8.000000e-10
GCST007927_29	Medication use (beta blocking agents)	5.000000e-08
GCST008760_4	Perceived sweetness of sucrose	4.000000e-06
GCST010463_15	Childhood ALL/LBL (acute lymphoblastic leukemia/lymphoblastic lymphoma) treatment-related venous thromboembolism	4.000000e-06
GCST010866_132	Coronary artery disease	1.000000e-08
GCST90002404_323	Red cell distribution width	3.000000e-14

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004330	coffee consumption
EFO:0007677	LDL peak particle diameter measurement
EFO:0007678	total fat intake measurement
EFO:0006335	systolic blood pressure
EFO:0009929	Beta blocking agent use measurement
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, increases expression, affects cotreatment	5
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Diethylhexyl Phthalate	decreases expression, increases abundance, increases methylation	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, increases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects expression	1
kojic acid	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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