LAMB2

protein-coding

laminin subunit beta 2, the group of Laminin subunits

Gene summary

Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the beta chain isoform laminin, beta 2. The beta 2 chain contains the 7 structural domains typical of beta chains of laminin, including the short alpha region. However, unlike beta 1 chain, beta 2 has a more restricted tissue distribution. It is enriched in the basement membrane of muscles at the neuromuscular junctions, kidney glomerulus and vascular smooth muscle. Transgenic mice in which the beta 2 chain gene was inactivated by homologous recombination, showed defects in the maturation of neuromuscular junctions and impairment of glomerular filtration. Alternative splicing involving a non consensus 5' splice site (gc) in the 5' UTR of this gene has been reported. It was suggested that inefficient splicing of this first intron, which does not change the protein sequence, results in a greater abundance of the unspliced form of the transcript than the spliced form. The full-length nature of the spliced transcript is not known. [provided by RefSeq, Aug 2011]

Previous symbols:

LAMS

MANE transcript

NM_002292.4

Inheritance

ClinVar variants

P:115U:742B:322

Top phenotype

Pierson syndrome; Nephrotic syndrome, type 5, with or without ocular abnormalities

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr3:49,121,114-49,133,118

External References & Databases

Ensembl (ENSG00000172037)

Transcript & Mutation Effects

hg38 • Region Span ~12.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

LAMB2-related infantile-onset nephrotic syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013621

Submitter: PanelApp Australia

Pierson syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012184

Submitter: Orphanet

Pierson syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012184

Submitter: PanelApp Australia

LAMB2-related infantile-onset nephrotic syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013621

Submitter: Labcorp Genetics (formerly Invitae)

Pierson syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012184

Submitter: G2P

LAMB2-related infantile-onset nephrotic syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013621

Submitter: G2P

Clinical Genomic Database (CGD)

Pierson syndrome; Nephrotic syndrome, type 5, with or without ocular abnormalitiesAR

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Chronic renal dialysis can extend life of affected individuals

Refs: 14136829; 15367484; 16912710; 17256789; 19251977; 21236492

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LAMB2 variants in ClinVar

15 Conditions Cataloged

Pierson syndromeTotal: 1132

LAMB2-related infantile-onset nephrotic syndromeTotal: 1125

Inborn genetic diseasesTotal: 288

not providedTotal: 180

not specifiedTotal: 76

LAMB2-related disorderTotal: 69

Nephrotic syndromeTotal: 13

Focal segmental glomerulosclerosisTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002292.4. 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			22 clinvar	262 clinvar		284
missense	2 clinvar	10 clinvar	706 clinvar	59 clinvar	1 clinvar	778
nonsense	17 clinvar	13 clinvar	2 clinvar			32
start loss		1 clinvar				1
frameshift	28 clinvar	18 clinvar	2 clinvar			48
splice donor/acceptor (+/-2bp)	5 clinvar	21 clinvar	10 clinvar			36
Total	52	63	742	321	1	1179

Highest pathogenic variant AF is 0.00008304917

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002292.4	RefSeq	NP_002283.3	32	MANE Select
ENST00000305544.9	Ensembl	ENSP00000307156.4	32	MANE Select
ENST00000418109.5	Ensembl	ENSP00000388325.1	32	Standard
ENST00000418109.6	Ensembl	ENSP00000388325.1	32	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lamb2	Danio rerio	Structure: slow muscle cell Quality: retracted abnormal

Gene / Model

Organism

Observed Phenotype

lamb2

Danio rerio

Structure: slow muscle cell

Quality: retracted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Small cell lung cancer - Homo sapiens (human)
Amoebiasis - Homo sapiens (human)

Biological Process

cell adhesion
axon guidance
neuromuscular junction development
visual perception
astrocyte development

Molecular Function

integrin binding
structural molecule activity
extracellular matrix structural constituent

Cellular Component

extracellular region
basement membrane
laminin-3 complex
endoplasmic reticulum lumen
neuromuscular junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000418109
Coding exons: 32
Length: 12005
Individuals with no LoFs: 125607
Homozygous LoFs: 0
Heterozygous LoFs: 141
Defined: 125748
p: 0.000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.775	994	1.07e+3	0.933	0.0000733	11606
Missense (PolyPhen)		359	435.66	0.82403		4865
Synonymous	0.628	385	401	0.960	0.0000226	3715
Loss of Function	4.29	46	89.9	0.512	0.00000562	946

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00092	0.00092	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00067	0.00067	rare
South Asian	0.00049	0.00049	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.;
Disease: DISEASE: Pierson syndrome (PIERSS) [MIM:609049]: Characterized by nephrotic syndrome with neonatal onset, diffuse mesangial sclerosis and eye abnormalities with microcoria as the leading clinical feature. Death usually occurs within the first weeks of life. Disease severity depends on the mutation type: nontruncating LAMB2 mutations may display variable phenotypes ranging from a milder variant of Pierson syndrome to isolated congenital nephrotic syndrome. {ECO:0000269|PubMed:15367484, ECO:0000269|PubMed:16912710}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nephrotic syndrome 5 with or without ocular abnormalities (NPHS5) [MIM:614199]: A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. NPHS5 is characterized by very early onset of progressive renal failure. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus. {ECO:0000269|PubMed:20798252, ECO:0000269|PubMed:21236492}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.419

Intolerance Scores

LoFtool: 0.840
RVIS EVS: -1.46
RVIS percentile EVS: 3.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.697

Gene Damage Prediction

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