C2CD4B

Summary

C2CD4B (C2 calcium dependent domain containing 4B, HGNC:33628) is a protein-coding gene on chromosome 15q22.2, encoding C2 calcium-dependent domain-containing protein 4B (A6NLJ0). May be involved in inflammatory process.

Involved in positive regulation of acute inflammatory response; regulation of cell adhesion; and regulation of vascular permeability involved in acute inflammatory response. Predicted to be located in nucleus.

Source: NCBI Gene 388125 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 108 total
• MANE Select transcript: NM_001007595

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33628
Approved symbol	C2CD4B
Name	C2 calcium dependent domain containing 4B
Location	15q22.2
Locus type	gene with protein product
Status	Approved
Aliases	NLF2
Ensembl gene	ENSG00000205502
Ensembl biotype	protein_coding
OMIM	610344
Entrez	388125

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000380392, ENST00000948855

RefSeq mRNA: 1 — MANE Select: NM_001007595 NM_001007595

CCDS: CCDS32259

Canonical transcript exons

ENST00000380392 — 2 exons

Exon	Start	End
ENSE00001484763	62163535	62165024
ENSE00001484765	62165195	62165285

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 91.11.

FANTOM5 (CAGE): breadth broad, TPM avg 11.0212 / max 916.1824, expressed in 436 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150368	11.0212	436

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	91.11	gold quality
tendon of biceps brachii	UBERON:0008188	88.17	silver quality
pancreas	UBERON:0001264	86.31	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.49	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.91	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	83.73	gold quality
body of stomach	UBERON:0001161	81.07	gold quality
omental fat pad	UBERON:0010414	80.61	gold quality
peritoneum	UBERON:0002358	80.56	gold quality
islet of Langerhans	UBERON:0000006	79.73	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.71	gold quality
pancreatic ductal cell	CL:0002079	78.91	silver quality
stomach	UBERON:0000945	77.27	gold quality
cartilage tissue	UBERON:0002418	76.35	gold quality
parotid gland	UBERON:0001831	76.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.78	silver quality
gingival epithelium	UBERON:0001949	74.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.69	gold quality
nasal cavity mucosa	UBERON:0001826	74.34	gold quality
fundus of stomach	UBERON:0001160	74.21	gold quality
buccal mucosa cell	CL:0002336	73.89	gold quality
gingiva	UBERON:0001828	73.83	gold quality
biceps brachii	UBERON:0001507	72.70	gold quality
vastus lateralis	UBERON:0001379	72.36	gold quality
adipose tissue	UBERON:0001013	72.21	gold quality
nasal cavity epithelium	UBERON:0005384	72.19	gold quality
mucosa of stomach	UBERON:0001199	71.81	gold quality
endometrium	UBERON:0001295	71.68	gold quality
quadriceps femoris	UBERON:0001377	71.10	gold quality
subcutaneous adipose tissue	UBERON:0002190	70.90	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	30.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting C2CD4B, 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-1193	100.00	65.93	529
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-3691-5P	98.62	65.88	552
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-7855-5P	97.39	67.18	925

Literature-anchored findings (GeneRIF, showing 7)

• NLF2 may play a role in regulating genes which control cellular architecture. (PMID:15527968)
• Single nucleotide polymorphism in C2CD4B is associated with type 2 diabetes. (PMID:20818381)
• Loss of NLF2 gene expression in the endometrium of patients with implantation failure after in vitro ertilization treatment. (PMID:22885067)
• The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered type 2 diabetes risk at this locus, particularly in females, and suggest that C2CD4A, but not C2CD4B, may also be involved. (PMID:27329800)
• rs7163757 contributes to genetic risk of islet dysfunction and type 2 diabetes by increasing NFAT-mediated islet enhancer activity and modulating C2CD4B, and possibly C2CD4A, expression in (patho)physiologic states. (PMID:29625024)
• C2CD4A/B variants in the predisposition of lung cancer in the Chinese Han population. (PMID:35212842)
• Selective Transcription Factor Blockade Reduces Human Retinal Endothelial Cell Expression of Intercellular Adhesion Molecule-1 and Leukocyte Binding. (PMID:36834715)

Cross-species orthologs

0 orthologs

Paralogs (31): SYT7 (ENSG00000011347), SYT13 (ENSG00000019505), SYT1 (ENSG00000067715), RPH3A (ENSG00000089169), SYTL4 (ENSG00000102362), SYT17 (ENSG00000103528), SYT10 (ENSG00000110975), SYT5 (ENSG00000129990), SYT11 (ENSG00000132718), SYT4 (ENSG00000132872), SYT6 (ENSG00000134207), SYTL2 (ENSG00000137501), SYT16 (ENSG00000139973), SYTL1 (ENSG00000142765), SYT14 (ENSG00000143469), SYT2 (ENSG00000143858), SYTL5 (ENSG00000147041), SYT8 (ENSG00000149043), DOC2A (ENSG00000149927), SYTL3 (ENSG00000164674), TC2N (ENSG00000165929), SYT9 (ENSG00000170743), SYT12 (ENSG00000173227), RPH3AL (ENSG00000181031), C2CD4C (ENSG00000183186), C2CD4A (ENSG00000198535), SYT15 (ENSG00000204176), SYT3 (ENSG00000213023), C2CD4D (ENSG00000225556), DOC2B (ENSG00000272636), SYT15B (ENSG00000277758)

Protein

Protein identifiers

C2 calcium-dependent domain-containing protein 4B — A6NLJ0 (reviewed: A6NLJ0)

Alternative names: Nuclear-localized factor 2, Protein FAM148B

All UniProt accessions (1): A6NLJ0

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in inflammatory process. May regulate cell architecture and adhesion.

Subcellular location. Nucleus.

Tissue specificity. Specifically expressed in endothelial cells.

Induction. Up-regulated by pro-inflammatory cytokines.

Similarity. Belongs to the C2CD4 family.

RefSeq proteins (1): NP_001007596* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR039208	C2_Ca-dependent_4	Family

UniProt features (7 total): region of interest 2, sequence variant 2, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NLJ0-F1	60.81	0.12

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 55 (showing top): GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_VASCULAR_PERMEABILITY, GOBP_VASCULAR_PROCESS_IN_CIRCULATORY_SYSTEM, MIKKELSEN_NPC_HCP_WITH_H3K4ME3_AND_H3K27ME3, chr15q22, GHANDHI_DIRECT_IRRADIATION_UP

GO Biological Process (3): regulation of vascular permeability involved in acute inflammatory response (GO:0002528), positive regulation of acute inflammatory response (GO:0002675), regulation of cell adhesion (GO:0030155)

GO Molecular Function (0):

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
acute inflammatory response	2
regulation of vascular permeability	1
regulation of acute inflammatory response	1
positive regulation of inflammatory response	1
cell adhesion	1
regulation of cellular process	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C2CD4B	RND1	Q92730	764
C2CD4B	DGKB	Q9Y6T7	669
C2CD4B	MTNR1B	P49286	625
C2CD4B	CDC123	O75794	608
C2CD4B	SLC30A8	Q8IWU4	608
C2CD4B	GLIS3	Q8NEA6	595
C2CD4B	AGMO	Q6ZNB7	594
C2CD4B	VPS13C	Q709C8	582
C2CD4B	ADCY5	O95622	580
C2CD4B	UBE2E2	Q96LR5	580
C2CD4B	ADRA2A	P08913	570
C2CD4B	CDKAL1	Q5VV42	544
C2CD4B	TCF7L2	Q9NQB0	543
C2CD4B	ARAP1	Q96P48	517
C2CD4B	OR13C5	Q8NGS8	507

IntAct

8 interactions, top by confidence:

A	B	Type	Score
MPDZ	SMCHD1	psi-mi:“MI:0914”(association)	0.590
ADAMTS13	C2CD4B	psi-mi:“MI:0914”(association)	0.350
PLXNB2	C2CD4B	psi-mi:“MI:0914”(association)	0.350
SCN4A	C2CD4B	psi-mi:“MI:0914”(association)	0.350
ALPK2	C2CD4B	psi-mi:“MI:0914”(association)	0.350
SVIL	C2CD4B	psi-mi:“MI:0914”(association)	0.350
C2CD4B	ZSWIM8	psi-mi:“MI:0914”(association)	0.350

BioGRID (44): TCF25 (Affinity Capture-MS), ZSWIM8 (Affinity Capture-MS), ZNF496 (Affinity Capture-MS), ARMCX3 (Affinity Capture-MS), DICER1 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), PCDH7 (Affinity Capture-MS), PHKB (Affinity Capture-MS), LRP1B (Affinity Capture-MS), APBA2 (Affinity Capture-MS), PASK (Affinity Capture-MS), MPP5 (Affinity Capture-MS), INADL (Affinity Capture-MS), ERBB2IP (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A286YF58, A0A2R8YCJ5, A0A7I2V3R4, A2A699, A2VDX9, A6NCS6, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NLJ0, A8MVW0, B2RU40, B7Z1M9, B8ZZ34, C9JH25, C9JVW0, D4A9R4, J3QNX5, M0QZC1, P03971, P0CG09, P0DPE3, Q0PHV7, Q0VD38, Q14761, Q29RK8, Q29RM6, Q2KJ18, Q2M3G4, Q2M3V2, Q5T442, Q64697, Q69YZ2, Q6F5E0, Q6NY19, Q6UXK2, Q80XF7

Diamond homologs: A6NLJ0, B7Z1M9, P0CG09, Q2KJ18, Q5HZI2, Q8NCU7, Q8TF44, Q17RD7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	100
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

86 predictions. Top by Δscore:

Variant	Effect	Δscore
15:62165020:TGCGC:T	acceptor_gain	0.9900
15:62165022:CGC:C	acceptor_gain	0.9900
15:62165025:C:CC	acceptor_gain	0.9900
15:62165026:T:A	acceptor_loss	0.9900
15:62165190:CAGAC:C	donor_loss	0.9800
15:62165191:AGACC:A	donor_loss	0.9800
15:62165193:A:C	donor_loss	0.9800
15:62165194:C:CT	donor_loss	0.9800
15:62165023:GC:G	acceptor_gain	0.9700
15:62165024:CC:C	acceptor_gain	0.9700
15:62165028:C:CT	acceptor_gain	0.9700
15:62165021:GCGC:G	acceptor_gain	0.9600
15:62165022:CGCC:C	acceptor_gain	0.9600
15:62165029:G:T	acceptor_gain	0.9600
15:62165194:CCTTT:C	donor_gain	0.9500
15:62165027:G:C	acceptor_loss	0.9300
15:62165153:T:TA	donor_gain	0.9200
15:62165195:C:G	donor_loss	0.9200
15:62165160:C:A	donor_gain	0.9000
15:62165205:T:TA	donor_gain	0.8900
15:62165168:C:T	donor_gain	0.8100
15:62165021:GCGCC:G	acceptor_gain	0.7700
15:62165022:CGCCT:C	acceptor_gain	0.7700
15:62165023:GCCTG:G	acceptor_gain	0.7700
15:62165024:CCTGC:C	acceptor_gain	0.7700
15:62165170:A:AC	donor_gain	0.7700
15:62165171:C:CC	donor_gain	0.7700
15:62165193:A:AC	donor_gain	0.6200
15:62165194:C:CC	donor_gain	0.6200
15:62165198:T:A	donor_gain	0.6200

AlphaMissense

2249 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:62164886:G:C	F33L	0.993
15:62164886:G:T	F33L	0.993
15:62164888:A:G	F33L	0.993
15:62164685:G:C	F100L	0.983
15:62164685:G:T	F100L	0.983
15:62164687:A:G	F100L	0.983
15:62164896:A:G	I30T	0.981
15:62164667:G:C	S106R	0.967
15:62164667:G:T	S106R	0.967
15:62164669:T:G	S106R	0.967
15:62164213:A:G	Y258H	0.947
15:62164887:A:G	F33S	0.946
15:62164686:A:G	F100S	0.944
15:62164887:A:C	F33C	0.943
15:62164212:T:C	Y258C	0.942
15:62164881:A:G	I35T	0.941
15:62164212:T:G	Y258S	0.932
15:62164896:A:C	I30S	0.929
15:62163984:A:T	V334D	0.927
15:62164649:C:A	K112N	0.925
15:62164649:C:G	K112N	0.925
15:62164654:G:T	R111S	0.923
15:62164922:G:C	F21L	0.918
15:62164922:G:T	F21L	0.918
15:62164924:A:G	F21L	0.918
15:62164191:A:T	L265H	0.912
15:62164213:A:C	Y258D	0.912
15:62164893:G:T	P31H	0.909
15:62164698:G:A	T96I	0.908
15:62164749:T:C	D79G	0.903

dbSNP variants (sampled 300 via entrez): RS1000120400 (15:62164404 C>A,G,T), RS1000412171 (15:62164233 G>C,T), RS1001015608 (15:62163186 T>C), RS1001109770 (15:62165901 G>C,T), RS1001175877 (15:62164043 G>A,C,T), RS1001231676 (15:62163807 A>G), RS1001446279 (15:62164819 G>A,C), RS1001530312 (15:62163399 C>G), RS1002883300 (15:62163761 G>C), RS1003757516 (15:62166391 C>T), RS1005580593 (15:62163809 A>G), RS1005584448 (15:62164634 G>A), RS1006928394 (15:62164280 C>A), RS1007677187 (15:62165496 G>C), RS1007898316 (15:62164276 G>A,C)

Disease associations

OMIM: gene MIM:610344 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): megacolon (MONDO:0001273)

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000568_2	Fasting blood glucose	4.000000e-08
GCST000787_1	Type 2 diabetes	9.000000e-14
GCST000796_4	Type 2 diabetes	7.000000e-07
GCST001173_2	Type 2 diabetes	8.000000e-06
GCST001212_4	Proinsulin levels	4.000000e-20
GCST002128_10	Type 2 diabetes	1.000000e-06
GCST007096_75	Pulse pressure	3.000000e-15
GCST007097_114	Pulse pressure	2.000000e-06
GCST007097_115	Pulse pressure	7.000000e-08
GCST007446_48	vWF levels	1.000000e-07
GCST007446_55	vWF levels	1.000000e-08
GCST008109_4	Fasting blood proinsulin levels	7.000000e-18
GCST008839_440	Height	2.000000e-13
GCST009379_204	Type 2 diabetes	3.000000e-13
GCST010107_11	L-selectin levels	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004467	insulin measurement
EFO:0005763	pulse pressure measurement
EFO:0008202	L-Selectin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
Silicon Dioxide	affects expression, increases expression	2
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenate	decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression, decreases reaction	1
clothianidin	increases expression	1
3,4,5,4’-tetramethoxystilbene	affects expression	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Lipopolysaccharides	decreases reaction, increases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1
Particulate Matter	increases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04340856	Not specified	COMPLETED	Retrospective, Uncontrolled Cohort Study on the Therapy of Chronic Megalon
NCT07470892	Not specified	NOT_YET_RECRUITING	Preoperative Fish Oil PN and Prognosis After Constipation Surgery