FBLN2

protein-coding

fibulin 2, the group of Fibulins

Gene summary

This gene encodes an extracellular matrix protein, which belongs to the fibulin family. This protein binds various extracellular ligands and calcium. It may play a role during organ development, in particular, during the differentiation of heart, skeletal and neuronal structures. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001004019.2

Inheritance

ClinVar variants

U:242B:14

Top phenotype

Pulmonary arterial hypertension

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr3:13,549,125-13,638,422

External References & Databases

Ensembl (ENSG00000163520)

Transcript & Mutation Effects

hg38 • Region Span ~89.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*FBLN2* was first reported in relation to autosomal dominant congenital heart disease in 2012 (Ackerman et al., PMID:23040494). One proband with a truncating variant reported in a publication was included in this curation (PMID: 33084842). This gene-disease relationship is supported by expression studies and biochemical function study (PMIDs: 7851641, 11507771, 21743496). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 11/27/2023 (SOP Version 10)

pulmonary arterial hypertensionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

FBLN2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2021 (Zhu et al., PMID: 33971972) in a case control study. Out of a cohort of 1647 idiopathic PAH cases, 3 rare predicted deleterious missense variants were identified in 6 unrelated individuals with one variant recurrent in four individuals. The relationship between FBLN2 and PAH is also supported by expression evidence from GTEx bulk tissue expression. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen PH Gene Curation Expert Panel on 8/30/2022 (SOP Version 9).

pulmonary arterial hypertensionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBLN2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 237

not providedTotal: 6

Pulmonary arterial hypertensionTotal: 1

Erythrocytosis, familial, 4Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001004019.2. 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			2 clinvar	3 clinvar	3 clinvar	8
missense			236 clinvar	6 clinvar	2 clinvar	244
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	242	9	5	256

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001004019.2	RefSeq	NP_001004019.1	17	MANE Select
ENST00000404922.8	Ensembl	ENSP00000384169.3	17	MANE Select
NM_001165035.2	RefSeq	NP_001158507.1	17	Standard
NM_001998.3	RefSeq	NP_001989.2	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Extracellular matrix organization
Molecules associated with elastic fibres
Elastic fibre formation

Biological Process

positive regulation of cell-substrate adhesion
extracellular matrix organization

Molecular Function

extracellular matrix structural constituent
calcium ion binding
extracellular matrix constituent conferring elasticity
extracellular matrix binding

Cellular Component

extracellular region
extracellular matrix
collagen-containing extracellular matrix
extracellular vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000404922
Coding exons: 17
Length: 106099
Individuals with no LoFs: 124641
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 124678
p: 0.000148

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.766	705	765	0.922	0.0000504	7887
Missense (PolyPhen)		257	336.92	0.7628		3615
Synonymous	0.624	320	335	0.957	0.0000248	2450
Loss of Function	4.38	19	53.6	0.354	0.00000282	591

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00026	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00012	0.00011	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Its binding to fibronectin and some other ligands is calcium dependent. May act as an adapter that mediates the interaction between FBN1 and ELN (PubMed:17255108). {ECO:0000269|PubMed:17255108}.;

Recessive Scores

pRec: 0.225

Intolerance Scores

LoFtool: 0.0720
RVIS EVS: -1.09
RVIS percentile EVS: 6.99

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.586

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium