NBEAL2

protein-coding

neurobeachin like 2, the group of BEACH domain containing |Armadillo like helical domain containing|WD repeat domain containing

Gene summary

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. [provided by RefSeq, Dec 2011]

MANE transcript

NM_015175.3

Inheritance

AD, AR

ClinVar variants

P:80U:626B:195

Top phenotype

Gray platelet syndrome

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr3:46,979,666-47,009,704

External References & Databases

Ensembl (ENSG00000160796)

Transcript & Mutation Effects

hg38 • Region Span ~30.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

gray platelet syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007686

Submitter: Orphanet

gray platelet syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007686

Submitter: PanelApp Australia

gray platelet syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007686

Submitter: ClinGen

NBEAL2 was first reported in relation to autosomal recessive gray platelet syndrome (GPS) by three publications in 2011 (Albers CA, et al., 2011, PMID: 21765411; Gunay-Aygun M, et al., 2011, PMID: 21765412; Kahr WH, et al., 2011, PMID: 21765413). At least 46 unique variants (e.g. missense, nonsense, frameshift, splice site, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 17 probands in 4 publications (PMIDs: 21765411, 21765412, 21765413, 23100277). Variants in this gene segregated with disease in 15 family members. More evidence is available in the literature, but the maximum score for genetic evidence (12pts) has been reached. This gene-disease relationship is supported by its expression in relevant tissues (PMID: 21765411) and the functional alteration observed in patient cells which address the causes of reduced platelet count and increased platelet size that characterize GPS (PMID: 26987485). Further support is provided by animal models in zebrafish (PMID: 21765411), and strong recapitulation of GPS in a mouse model (PMID: 23861251). In summary, NBEAL2 is definitively associated with autosomal recessive inheritance of gray platelet syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

gray platelet syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007686

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Gray platelet syndromeAR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals may manifest with anemia (sometimes requiring RBC transfusions) due to bleeding tendencies, and preventive measures and treatment (eg, when surgery is needed) may be beneficial; Recognition of the development of myelofibrosis may also be beneficial in order to allow prompt management

Refs: 5129551; 6156948; 3414674; 8192152; 20709904; 21765411; 21765412; 21765413; 23100277

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NBEAL2 variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 450

Gray platelet syndromeTotal: 264

not providedTotal: 252

not specifiedTotal: 207

NBEAL2-related disorderTotal: 110

ThrombocytopeniaTotal: 7

Abnormal bleedingTotal: 6

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015175.3. 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			34 clinvar	137 clinvar	5 clinvar	176
missense	3 clinvar	10 clinvar	572 clinvar	51 clinvar		636
nonsense	9 clinvar	12 clinvar	2 clinvar			23
start loss						0
frameshift	13 clinvar	18 clinvar	1 clinvar	1 clinvar	1 clinvar	34
splice donor/acceptor (+/-2bp)	6 clinvar	9 clinvar	17 clinvar			32
Total	31	49	626	189	6	901

Highest pathogenic variant AF is 0.000013698086

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015175.3	RefSeq	NP_055990.1	54	MANE Select
ENST00000450053.8	Ensembl	ENSP00000415034.2	54	MANE Select
NM_001365116.2	RefSeq	NP_001352045.1	53	Standard
ENST00000416683.5	Ensembl	ENSP00000410405.1	40	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nbeal2	Danio rerio	Structure: post-vent region Quality: hemorrhagic abnormal

Gene / Model

Organism

Observed Phenotype

nbeal2

Danio rerio

Structure: post-vent region

Quality: hemorrhagic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neutrophil degranulation
Innate Immune System
Immune System

Biological Process

platelet formation
neutrophil degranulation

Molecular Function

protein binding

Cellular Component

endoplasmic reticulum
plasma membrane
tertiary granule membrane
ficolin-1-rich granule membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000450053
Coding exons: 54
Length: 30021
Individuals with no LoFs: 124761
Homozygous LoFs: 3
Heterozygous LoFs: 534
Defined: 125298
p: 0.00215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.39	1385	1.66e+3	0.835	0.000109	17378
Missense (PolyPhen)		312	459.62	0.67882		5098
Synonymous	0.00237	706	706	1.00	0.0000450	5970
Loss of Function	8.09	31	131	0.237	0.00000678	1390

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0063	0.0060	notable
Latino/Admixed American	0.00083	0.00081	rare
Ashkenazi Jewish	0.00081	0.00079	rare
East Asian	0.00080	0.00071	rare
Finnish	0.00054	0.00051	rare
European (Non-Finnish)	0.00055	0.00053	rare
South Asian	0.011	0.010	notable
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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. {ECO:0000269|PubMed:21765411, ECO:0000269|PubMed:21765412}.;

Intolerance Scores

LoFtool: 0.763
RVIS EVS: -3.12
RVIS percentile EVS: 0.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.141

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High