NBEAL2

Summary

NBEAL2 (neurobeachin like 2, HGNC:31928) is a protein-coding gene on chromosome 3p21.31, encoding Neurobeachin-like protein 2 (Q6ZNJ1). Probably involved in thrombopoiesis.

The protein encoded by this gene contains a beige and Chediak-Higashi (BEACH) domain and multiple WD40 domains, and may play a role in megakaryocyte alpha-granule biogenesis. Mutations in this gene are a cause of gray platelet syndrome.

Source: NCBI Gene 23218 — RefSeq curated summary.

At a glance

• Gene–disease (curated): gray platelet syndrome (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 943 total — 34 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 18
• MANE Select transcript: NM_015175

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31928
Approved symbol	NBEAL2
Name	neurobeachin like 2
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0540
Ensembl gene	ENSG00000160796
Ensembl biotype	protein_coding
OMIM	614169
Entrez	23218

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 11 retained_intron, 7 protein_coding, 1 nonsense_mediated_decay

ENST00000416683, ENST00000423436, ENST00000441027, ENST00000443829, ENST00000450053, ENST00000461036, ENST00000469349, ENST00000475689, ENST00000476095, ENST00000477412, ENST00000486870, ENST00000651350, ENST00000651450, ENST00000651453, ENST00000651747, ENST00000652242, ENST00000652744, ENST00000933460, ENST00000952756

RefSeq mRNA: 2 — MANE Select: NM_015175 NM_001365116, NM_015175

CCDS: CCDS46817, CCDS93260

Canonical transcript exons

ENST00000450053 — 54 exons

Exon	Start	End
ENSE00001054519	47006333	47006449
ENSE00001054528	47002645	47002802
ENSE00001054529	47002957	47003081
ENSE00001054530	47003174	47003309
ENSE00001054532	47004495	47004590
ENSE00001054539	47003816	47003976
ENSE00001054542	47004077	47004393
ENSE00001078653	47007066	47007155
ENSE00001078654	47009219	47009701
ENSE00001078656	47008989	47009124
ENSE00001078658	47007241	47007350
ENSE00001078659	47007525	47007697
ENSE00001208547	47004972	47005096
ENSE00003465479	46997561	46997694
ENSE00003468665	47007816	47007910
ENSE00003470410	47001920	47002288
ENSE00003472625	46989085	46989166
ENSE00003474247	46996271	46996592
ENSE00003497388	46995032	46995633
ENSE00003499427	46993937	46994020
ENSE00003507404	47005738	47005847
ENSE00003508591	46998067	46998226
ENSE00003511106	46995714	46995846
ENSE00003520522	46996954	46997046
ENSE00003520711	47005181	47005321
ENSE00003523009	47002371	47002520
ENSE00003527403	47005946	47006063
ENSE00003531143	46995932	46996051
ENSE00003535799	46991219	46991304
ENSE00003544755	46998717	46998879
ENSE00003544923	46988669	46988757
ENSE00003547439	47001279	47001438
ENSE00003549777	46992475	46992555
ENSE00003559323	46988842	46988970
ENSE00003559369	47005489	47005619
ENSE00003591314	46994455	46994553
ENSE00003591408	47008520	47008668
ENSE00003591495	47006165	47006262
ENSE00003595033	46997259	46997433
ENSE00003595933	47008070	47008186
ENSE00003600274	46999889	47000404
ENSE00003602014	46996751	46996833
ENSE00003613130	47008283	47008441
ENSE00003613755	47001001	47001179
ENSE00003616046	47001689	47001826
ENSE00003623183	46979666	46979912
ENSE00003642252	46998959	46999117
ENSE00003646505	46991406	46991688
ENSE00003648557	46989511	46989593
ENSE00003658269	46999315	46999474
ENSE00003664515	46999630	46999715
ENSE00003666276	46989260	46989381
ENSE00003668945	46998463	46998565
ENSE00003693915	46991840	46991946

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.5213 / max 634.0545, expressed in 1659 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36516	6.4734	1285
36519	5.7956	531
36515	2.6435	893
36514	2.1265	1030
36513	1.4038	800
36521	0.4147	140
36518	0.3156	91
36520	0.2234	89
36522	0.1247	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.33	gold quality
lower esophagus mucosa	UBERON:0035834	99.11	gold quality
skin of abdomen	UBERON:0001416	98.64	gold quality
skin of leg	UBERON:0001511	98.63	gold quality
upper lobe of left lung	UBERON:0008952	98.26	gold quality
right lung	UBERON:0002167	98.02	gold quality
esophagus mucosa	UBERON:0002469	97.96	gold quality
metanephros cortex	UBERON:0010533	97.67	gold quality
body of pancreas	UBERON:0001150	97.30	gold quality
upper lobe of lung	UBERON:0008948	97.25	gold quality
spleen	UBERON:0002106	97.10	gold quality
minor salivary gland	UBERON:0001830	97.05	gold quality
monocyte	CL:0000576	96.91	gold quality
mononuclear cell	CL:0000842	96.80	gold quality
leukocyte	CL:0000738	96.78	gold quality
body of stomach	UBERON:0001161	96.48	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.15	gold quality
mouth mucosa	UBERON:0003729	96.05	gold quality
gall bladder	UBERON:0002110	95.32	gold quality
mucosa of transverse colon	UBERON:0004991	95.18	gold quality
pharyngeal mucosa	UBERON:0000355	95.07	gold quality
apex of heart	UBERON:0002098	95.01	gold quality
blood	UBERON:0000178	95.00	gold quality
zone of skin	UBERON:0000014	94.99	gold quality
transverse colon	UBERON:0001157	94.85	gold quality
right uterine tube	UBERON:0001302	94.57	gold quality
lymph node	UBERON:0000029	94.56	gold quality
stomach	UBERON:0000945	94.51	gold quality
esophagus	UBERON:0001043	94.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.25	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	13.53
E-ANND-3	yes	12.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1

miRNA regulators (miRDB)

24 targeting NBEAL2, 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-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-558	97.50	67.16	977
HSA-MIR-4732-3P	97.15	65.45	881
HSA-MIR-7108-3P	94.37	64.79	183
HSA-MIR-4258	90.68	62.19	164

Literature-anchored findings (GeneRIF, showing 13)

• NBEAL2 mutation is associated with gray platelet syndrome. (PMID:21765411)
• NBEAL2 mutation is associated with gray platelet syndrome. (PMID:21765412)
• Mutations in NBEAL2, encoding a BEACH protein is associated with gray platelet syndrome. (PMID:21765413)
• we herein show a long-distance regulatory region with GATA1 binding sites as being a strong enhancer for NBEAL2 expression. (PMID:28082341)
• NBEAL2 has an essential role in neutrophil and NK cell function and pathogen defense (PMID:28783043)
• Nbeal2 interacts with Dock7, Sec16a, and Vac14. (PMID:29187380)
• Author observed absence of NBEAL2 in platelets from GPS patients with 3 different genotypes, and reduced/truncated platelet NBEAL2 has been reported for others. (PMID:29869935)
• NBEAL2 is required for the retention of both endocytosed and megakaryocyte-synthesized proteins by maturing alpha-granules, and possibly by platelet-borne granules. This function may involve interaction of NBEAL2 with P-selectin. (PMID:30354215)
• Defective Zn(2+) homeostasis in mouse and human platelets with alpha- and delta-storage pool diseases. (PMID:31171812)
• The endoplasmic reticulum protein SEC22B interacts with NBEAL2 and is required for megakaryocyte alpha-granule biogenesis. (PMID:32384141)
• Gray platelet syndrome: NBEAL2 mutations are associated with pathology beyond megakaryocyte and platelet function defects. (PMID:33300270)
• NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells. (PMID:37349339)
• The Neurobeachin-like 2 protein (NBEAL2) controls the homeostatic level of the ribosomal protein RPS6 in mast cells. (PMID:38272677)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nbeal2	ENSDARG00000098641
mus_musculus	Nbeal2	ENSMUSG00000056724
rattus_norvegicus	Nbeal2	ENSRNOG00000027880
caenorhabditis_elegans		WBGENE00004760
caenorhabditis_elegans		WBGENE00007752

Paralogs (7): NSMAF (ENSG00000035681), WDFY4 (ENSG00000128815), LYST (ENSG00000143669), NBEAL1 (ENSG00000144426), WDFY3 (ENSG00000163625), NBEA (ENSG00000172915), LRBA (ENSG00000198589)

Protein

Protein identifiers

Neurobeachin-like protein 2 — Q6ZNJ1 (reviewed: Q6ZNJ1)

All UniProt accessions (6): Q6ZNJ1, A0A494C1V1, H0Y764, H7C354, H7C3Y7, H7C408

UniProt curated annotations — full annotation on UniProt →

Function. Probably involved in thrombopoiesis. Plays a role in the development or secretion of alpha-granules, that contain several growth factors important for platelet biogenesis.

Subcellular location. Endoplasmic reticulum.

Tissue specificity. Expressed in megakaryocytes.

Disease relevance. Gray platelet syndrome (GPS) [MIM:139090] A rare platelet disorder characterized by a selective deficiency in the number and contents of platelet alpha-granules. It is associated with mild to moderate bleeding tendency and moderate thrombocytopenia. The platelets are enlarged and have a gray appearance on light microscopy of Wright-stained peripheral blood smears due to decreased granules. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the WD repeat neurobeachin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6ZNJ1-1	1	yes
Q6ZNJ1-2	2
Q6ZNJ1-3	3

RefSeq proteins (2): NP_001352045, NP_055990* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000409	BEACH_dom	Domain
IPR001680	WD40_rpt	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR023362	PH-BEACH_dom	Domain
IPR031570	NBEA/BDCP_DUF4704	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR036372	BEACH_dom_sf	Homologous_superfamily
IPR046851	NBCH_WD40	Domain
IPR046852	Neurobeachin_a-sol	Domain
IPR050865	BEACH_Domain	Family

Pfam: PF02138, PF14844, PF15787, PF16057, PF20425, PF20426

UniProt features (41 total): sequence variant 16, repeat 7, modified residue 4, compositionally biased region 3, splice variant 3, sequence conflict 3, domain 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q6ZNJ1 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Post-translational modifications (4): 1647, 1867, 2739, 2742

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 211 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, CHUNG_BLISTER_CYTOTOXICITY_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_PLATELET_MORPHOGENESIS, CROMER_TUMORIGENESIS_DN, GOCC_SECRETORY_VESICLE, GOCC_SECRETORY_GRANULE_MEMBRANE, SANSOM_APC_MYC_TARGETS, SANSOM_APC_TARGETS_REQUIRE_MYC, GARY_CD5_TARGETS_UP, WONG_ADULT_TISSUE_STEM_MODULE, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_QTL_TRANS

GO Biological Process (3): intracellular protein localization (GO:0008104), platelet formation (GO:0030220), myeloid cell differentiation (GO:0030099)

GO Molecular Function (2): protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), tertiary granule membrane (GO:0070821), ficolin-1-rich granule membrane (GO:0101003)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
secretory granule membrane	2
tertiary granule	2
macromolecule localization	1
myeloid cell differentiation	1
platelet morphogenesis	1
anatomical structure formation involved in morphogenesis	1
hemopoiesis	1
cell differentiation	1
kinase binding	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

932 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NBEAL2	VIPAS39	Q9H9C1	705
NBEAL2	VPS33B	Q9H267	642
NBEAL2	GP1BA	P07359	609
NBEAL2	GP9	P14770	567
NBEAL2	RBM8A	Q9Y5S9	550
NBEAL2	CGGBP1	Q9UFW8	546
NBEAL2	GFI1B	Q5VTD9	528
NBEAL2	CCDC12	Q8WUD4	524
NBEAL2	WDFY3	Q8IZQ1	508
NBEAL2	ANKRD26	Q9UPS8	507
NBEAL2	UNC13D	Q70J99	506
NBEAL2	GP1BB	P13224	479
NBEAL2	GATA1	P15976	460
NBEAL2	EPHB1	P54762	460
NBEAL2	TMEM51	Q9NW97	449

IntAct

42 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
NBEAL2	VAC14	psi-mi:“MI:0915”(physical association)	0.650
DOCK7	NBEAL2	psi-mi:“MI:0915”(physical association)	0.650
NBEAL2	DOCK7	psi-mi:“MI:2364”(proximity)	0.650
NBEAL2	VAC14	psi-mi:“MI:2364”(proximity)	0.650
NBEAL2	VAC14	psi-mi:“MI:0914”(association)	0.650
SEC16A	NBEAL2	psi-mi:“MI:0914”(association)	0.640
SEC16A	NBEAL2	psi-mi:“MI:0915”(physical association)	0.640
NBEAL2	SEC16A	psi-mi:“MI:0914”(association)	0.640
CD40	EXOC5	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
NBEAL2	NOP2	psi-mi:“MI:0915”(physical association)	0.400
NBEAL2	HAX1	psi-mi:“MI:0914”(association)	0.350
VAC14	SEC16A	psi-mi:“MI:0914”(association)	0.350
DOCK7	VAC14	psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
CSNK1G2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
SEMA4C	ARVCF	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Proximity Label-MS), NBEAL2 (Proximity Label-MS), NBEAL2 (Proximity Label-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS), NBEAL2 (Affinity Capture-MS)

ESM2 similar proteins: A0JMF1, A2CI97, A3KNA7, A6NE52, B2GV47, E7FAW3, P60330, Q06ZW3, Q0VDN7, Q12769, Q1M161, Q2NKJ3, Q2YDQ5, Q3SYW0, Q3T1I9, Q3U6Q4, Q4FZR5, Q5EE38, Q5PNP6, Q5RDX3, Q5SUQ9, Q5TYP4, Q5ZIB8, Q6AYM1, Q6DG91, Q6IRN0, Q6NSI4, Q6NYX6, Q6P4K6, Q6PH58, Q6ZNJ1, Q6ZPG2, Q6ZQA0, Q7T006, Q7ZVM9, Q80TE0, Q80VA5, Q8BJW5, Q8BMG1, Q8C779

Diamond homologs: A3LNM0, A5DNK9, A5DTA8, A6ZRQ4, P53877, Q15269, Q5AB15, Q5RFQ3, Q6BMP5, Q6C953, Q6ZNJ1, Q8BU03, Q9M3B4, A8XSV3, D4A929, E7FAW3, E9Q2M9, F4HZB2, F4IG73, F4JD14, F4JHT3, O35242, P0C6P0, P25356, P50851, P97412, Q19317, Q54PP7, Q54RQ8, Q55AV3, Q55DM1, Q562E7, Q5ND34, Q6VNB8, Q6ZQA0, Q6ZS30, Q6ZS81, Q7LKZ7, Q86JF2, Q8IZQ1

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
GATA1	“up-regulates quantity by expression”	NBEAL2	“transcriptional regulation”
NBEAL2	up-regulates	Platelet_morphogenesis
NBEAL2	up-regulates	Platelet_alpha_granule_formation
NBEAL2	up-regulates	VWF
NBEAL2	up-regulates	SELP
NBEAL2	down-regulates	IQGAP1
NBEAL2	“up-regulates activity”	DOCK7	binding
NBEAL2	unknown	VAC14	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	37
Uncertain significance	604
Likely benign	103
Benign	56

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1300139	NM_015175.3(NBEAL2):c.5476dup (p.Arg1826fs)	Pathogenic
1391899	NM_015175.3(NBEAL2):c.379C>T (p.Arg127Ter)	Pathogenic
2429388	NM_015175.3(NBEAL2):c.5301+1G>A	Pathogenic
2443319	NM_015175.3(NBEAL2):c.7460_7461del (p.Thr2487fs)	Pathogenic
2575410	NM_015175.3(NBEAL2):c.925+5del	Pathogenic
280483	NM_015175.3(NBEAL2):c.3592C>T (p.Gln1198Ter)	Pathogenic
31116	NM_015175.3(NBEAL2):c.2701C>T (p.Arg901Ter)	Pathogenic
31117	NM_015175.3(NBEAL2):c.881C>G (p.Ser294Ter)	Pathogenic
31118	NM_015175.3(NBEAL2):c.1163T>C (p.Leu388Pro)	Pathogenic
31119	NM_015175.3(NBEAL2):c.1928A>T (p.Glu643Val)	Pathogenic
31120	NM_015175.3(NBEAL2):c.6299C>T (p.Pro2100Leu)	Pathogenic
31121	NM_015175.3(NBEAL2):c.1823G>A (p.Trp608Ter)	Pathogenic
31122	NM_015175.3(NBEAL2):c.5413dup (p.Ala1805fs)	Pathogenic
3768691	NC_000003.11:g.(?47021155)(47021403_47030158)del	Pathogenic
4277723	NM_015175.3(NBEAL2):c.2953C>T (p.Arg985Ter)	Pathogenic
435927	NM_015175.3(NBEAL2):c.1793G>A (p.Trp598Ter)	Pathogenic
435928	NM_015175.3(NBEAL2):c.4081G>T (p.Glu1361Ter)	Pathogenic
4530588	NM_015175.3(NBEAL2):c.3222-2A>T	Pathogenic
627258	NM_015175.3(NBEAL2):c.1789C>T (p.Arg597Ter)	Pathogenic
627345	NM_015175.3(NBEAL2):c.607dup (p.Ile203fs)	Pathogenic
627372	NM_015175.3(NBEAL2):c.7387C>T (p.Gln2463Ter)	Pathogenic
812961	NM_015175.3(NBEAL2):c.3118+2T>G	Pathogenic
812962	NM_015175.3(NBEAL2):c.6432del (p.Phe2144fs)	Pathogenic
982270	NM_015175.3(NBEAL2):c.1725_1728dup (p.Ala577fs)	Pathogenic
982272	NM_015175.3(NBEAL2):c.2751dup (p.Asp918Ter)	Pathogenic
982274	NM_015175.3(NBEAL2):c.4928_4929del (p.Asp1643fs)	Pathogenic
982276	NM_015175.3(NBEAL2):c.7192_7202dup (p.Gln2402fs)	Pathogenic
982277	NM_015175.3(NBEAL2):c.4890del (p.Arg1631fs)	Pathogenic
982278	NM_015175.3(NBEAL2):c.7506del (p.Asp2503fs)	Pathogenic
982279	NM_015175.3(NBEAL2):c.6920-1G>C	Pathogenic

SpliceAI

8149 predictions. Top by Δscore:

Variant	Effect	Δscore
3:46979910:CAGG:C	donor_loss	1.0000
3:46979912:GGTG:G	donor_loss	1.0000
3:46979913:G:C	donor_loss	1.0000
3:46988757:GGTGA:G	donor_loss	1.0000
3:46988759:T:G	donor_loss	1.0000
3:46988838:GCA:G	acceptor_loss	1.0000
3:46988840:A:AC	acceptor_loss	1.0000
3:46988840:A:AG	acceptor_gain	1.0000
3:46988840:AG:A	acceptor_gain	1.0000
3:46988841:G:GA	acceptor_gain	1.0000
3:46988841:G:T	acceptor_loss	1.0000
3:46988841:GG:G	acceptor_gain	1.0000
3:46988841:GGC:G	acceptor_gain	1.0000
3:46988841:GGCC:G	acceptor_gain	1.0000
3:46988841:GGCCA:G	acceptor_gain	1.0000
3:46989164:G:GT	donor_gain	1.0000
3:46989378:GTGG:G	donor_gain	1.0000
3:46989400:G:GT	donor_gain	1.0000
3:46989510:GGGAA:G	acceptor_gain	1.0000
3:46991836:ACAG:A	acceptor_loss	1.0000
3:46991837:C:G	acceptor_gain	1.0000
3:46991838:A:AG	acceptor_gain	1.0000
3:46991838:AG:A	acceptor_loss	1.0000
3:46991838:AGAC:A	acceptor_gain	1.0000
3:46991839:G:GG	acceptor_gain	1.0000
3:46991839:GA:G	acceptor_gain	1.0000
3:46991839:GAC:G	acceptor_gain	1.0000
3:46991839:GACG:G	acceptor_gain	1.0000
3:46991839:GACGC:G	acceptor_gain	1.0000
3:46991942:GCAAG:G	donor_gain	1.0000

AlphaMissense

17647 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:47006233:T:C	F2330L	1.000
3:47006235:T:A	F2330L	1.000
3:47006235:T:G	F2330L	1.000
3:47004155:C:A	A1987E	0.999
3:47004498:T:A	W2068R	0.999
3:47004498:T:C	W2068R	0.999
3:47004500:G:C	W2068C	0.999
3:47004500:G:T	W2068C	0.999
3:47004541:T:C	L2082P	0.999
3:47004545:C:A	N2083K	0.999
3:47004545:C:G	N2083K	0.999
3:47004555:G:T	G2087W	0.999
3:47004559:G:C	R2088P	0.999
3:47004978:T:A	W2101R	0.999
3:47004978:T:C	W2101R	0.999
3:47005221:T:C	F2154L	0.999
3:47005223:C:A	F2154L	0.999
3:47005223:C:G	F2154L	0.999
3:47005236:C:G	H2159D	0.999
3:47005243:C:T	S2161F	0.999
3:47005506:G:C	R2193P	0.999
3:47005512:T:C	F2195S	0.999
3:47005979:T:A	W2279R	0.999
3:47005979:T:C	W2279R	0.999
3:47005989:T:C	L2282P	0.999
3:47006042:T:C	F2300L	0.999
3:47006044:C:A	F2300L	0.999
3:47006044:C:G	F2300L	0.999
3:47006225:T:A	I2327N	0.999
3:47006236:G:T	G2331W	0.999

dbSNP variants (sampled 300 via entrez): RS1000044113 (3:47006564 C>T), RS1000087957 (3:46994866 T>A), RS1000138698 (3:46987884 C>A,G,T), RS1000242537 (3:46983512 G>A), RS1000352403 (3:46984675 G>A,C), RS1000754089 (3:46989195 A>C,T), RS1000943136 (3:47001724 G>A,C), RS1001152771 (3:47001484 A>G,T), RS1001197939 (3:46984702 G>A,T), RS1001207491 (3:46989335 G>A,T), RS1001207796 (3:47009298 A>C), RS1001250282 (3:46985122 A>G), RS1001548932 (3:47003224 A>T), RS1001806385 (3:46982260 C>G), RS1001812545 (3:46990796 T>C)

Disease associations

OMIM: gene MIM:614169 | disease phenotypes: MIM:139090, MIM:148300

GenCC curated gene-disease

Disease	Classification	Inheritance
gray platelet syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
gray platelet syndrome	Definitive	AR

Mondo (3): gray platelet syndrome (MONDO:0007686), keratoconus (MONDO:0015486), thrombocytopenia (MONDO:0002049)

Orphanet (3): Gray platelet syndrome (Orphanet:721), OBSOLETE: Keratoconus (Orphanet:156071), NON RARE IN EUROPE: Isolated keratoconus (Orphanet:2335)

HPO phenotypes

18 total (19 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000140	Abnormality of the menstrual cycle
HP:0000421	Epistaxis
HP:0000978	Bruising susceptibility
HP:0001744	Splenomegaly
HP:0001872	Abnormality of thrombocytes
HP:0001873	Thrombocytopenia
HP:0001892	Abnormal bleeding
HP:0002863	Myelodysplasia
HP:0003010	Prolonged bleeding time
HP:0003676	Progressive
HP:0008320	Impaired collagen-induced platelet aggregation
HP:0008330	Reduced von Willebrand factor activity
HP:0011872	Impaired thrombin-induced platelet aggregation
HP:0011974	Myelofibrosis
HP:0012147	Reduced quantity of Von Willebrand factor
HP:0012528	Abnormal number of alpha granules
HP:0000563	Keratoconus

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003264_124	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST003264_888	Post bronchodilator FEV1/FVC ratio	5.000000e-06
GCST004691_3	Huntington’s disease progression	2.000000e-06
GCST010002_422	Refractive error	4.000000e-14
GCST90013407_84	Liver enzyme levels (gamma-glutamyl transferase)	4.000000e-27

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0008336	disease progression measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D055652	Gray Platelet Syndrome	C15.378.140.427; C16.320.099.417
D007640	Keratoconus	C11.204.627
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
bisphenol A	decreases expression, decreases methylation	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
FR900359	affects phosphorylation	1
bisphenol F	increases methylation, affects cotreatment	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vehicle Emissions	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0JV	SANi006-A	Induced pluripotent stem cell	Female
CVCL_TA04	HAP1 NBEAL2 (-) 1	Cancer cell line	Male
CVCL_TA05	HAP1 NBEAL2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01485211	PHASE4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	PHASE4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	PHASE4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	PHASE4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	PHASE4	COMPLETED	Corneal Crosslinking Treatment Study
NCT07474870	PHASE4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00371202	PHASE3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00647699	PHASE3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00815256	PHASE3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00887900	PHASE3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01112072	PHASE3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT01152541	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Progressive Keratoconus and Ectasia Using Riboflavin/Dextran and Hypotonic Riboflavin
NCT01190306	PHASE3	TERMINATED	Safety Study of the VEGA UV-A System to Treat Keratoconus
NCT01344187	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01459679	PHASE3	TERMINATED	Safety & Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery
NCT01464268	PHASE3	UNKNOWN	Transepithelial Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia
NCT01604135	PHASE3	ACTIVE_NOT_RECRUITING	Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial
NCT01643226	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01672814	PHASE3	COMPLETED	Microwave Treatment and Corneal Collagen Crosslinking for Keratoconus
NCT01682993	PHASE3	TERMINATED	Corneal Cross Linking and Topography Guided Excimer Laser Treatment
NCT01972854	PHASE3	TERMINATED	Safety and Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT02613780	PHASE3	UNKNOWN	Refractive Treatment of Early Keratoconus
NCT02638376	PHASE3	UNKNOWN	Evaluating the Safety and Efficacy of the KXL System for Corneal Collagen Cross-Linking in Eyes Having Keratoconus
NCT03080077	PHASE3	UNKNOWN	Safety and Effectiveness of Corneal Crosslinking (CXL): Keratoconus and Post-Refractive Ectasia
NCT03187912	PHASE3	COMPLETED	Accelerated Corneal Cross-linking With Different Riboflavin Solutions
NCT03442751	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus