BIN1

protein-coding

bridging integrator 1, the group of N-BAR domain containing

Gene summary

This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which was initially identified as a MYC-interacting protein with features of a tumor suppressor. Isoforms that are expressed in the central nervous system may be involved in synaptic vesicle endocytosis and may interact with dynamin, synaptojanin, endophilin, and clathrin. Isoforms that are expressed in muscle and ubiquitously expressed isoforms localize to the cytoplasm and nucleus and activate a caspase-independent apoptotic process. Studies in mouse suggest that this gene plays an important role in cardiac muscle development. Alternate splicing of the gene results in several transcript variants encoding different isoforms. Aberrant splice variants expressed in tumor cell lines have also been described. [provided by RefSeq, Mar 2016]

Previous symbols:

AMPHL

MANE transcript

NM_139343.3

Inheritance

AR, AD, SD

ClinVar variants

P:15U:319B:159

Top phenotype

Myopathy, centronuclear, 2

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr2:127,048,027-127,107,288

External References & Databases

Ensembl (ENSG00000136717)

Transcript & Mutation Effects

hg38 • Region Span ~59.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myopathy, centronuclear, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009709

Submitter: G2P

autosomal dominant centronuclear myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008048

Submitter: Orphanet

autosomal recessive centronuclear myopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015705

Submitter: Orphanet

myopathy, centronuclear, 2STRONG

Inheritance Pattern: SD

Disease ID:MONDO:0009709

Submitter: PanelApp Australia

myopathy, centronuclear, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009709

Submitter: Labcorp Genetics (formerly Invitae)

centronuclear myopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018947

Submitter: ClinGen

*BIN1* was first reported in relation to autosomal dominant centronuclear myopathy in 2014 (Böhm J, et al., 2014, PMID: 25260562). It is characterized by progressive adult-onset myopathy without facial weakness. Heterozygous ariants in the *BIN1* gene have been reported in seven patients with autosomal dominant centronuclear myopathy in three publications (PMIDs: 25260562, 27854204, 29103045). Seven unique variants have been reported, falling into two types either missense or single amino acid deletions in the N-terminal amphipathic helix, where a dominant negative effect has been observed (PMID: 25260562), or frameshifts near the C-terminus which extend the protein and may impact SH3 domain folding or interaction with other proteins. This gene-disease relationship is further supported by its biochemical function in the t-tublue system (PMID: 31857086), enhanced expression in skeletal muscle (PMID: 9182667), protein-protein interaction with *DNM2* (PMID: 15483625), and functional alteration in patient cells (Böhm J, et al., 2014, PMID: 25260562). 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. Of note, *BIN1* has also been reported in relation to autosomal recessive centronuclear myopathy. Due to the proposed difference in mechanism, loss of function, those cases were considered in a separate curation.

myopathy, centronuclear, 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009709

Submitter: Ambry Genetics

centronuclear myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018947

Submitter: ClinGen

*BIN1* was first reported in relation to autosomal recessive centronuclear myopathy in 2007 (Nicot AS, et al., 2007, PMID: 17676042). It is characterized by mild, proximal, slowly progressive muscle weakness with onset ranging from birth to childhood. Variants in the *BIN1* gene have been reported in over twenty patients with autosomal recessive centronuclear myopathy in five different publications (PMIDs: 20142620, 17676042, 23754947, 21129173, 29950440). Eight unique variants (nonsense, splice site, and missense) predicted to cause a loss of function of the protein have been reported, suggesting homozygous loss of function the mechanism of disease. This gene-disease relationship is further supported by its biochemical function in the t-tublue system (PMID: 31857086), enhanced expression in skeletal muscle (PMID: 9182667), protein-protein interaction with *DNM2* (PMID: 15483625), and animal model studies (PMIDs: 23754947, 29130937, 11711432, 24549043). In summary, *BIN1* is definitively associated with autosomal recessive centronuclear myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Of note, *BIN1* has also been reported in relation to autosomal dominant centronuclear myopathy. Due to the proposed difference in mechanism, dominant negative, those cases were considered in a separate curation.

Clinical Genomic Database (CGD)

Myopathy, centronuclear, 2AR

Manifestation: Musculoskeletal

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

Refs: 17676042; 20142620; 22392505

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BIN1 variants in ClinVar

7 Conditions Cataloged

Myopathy, centronuclear, 2Total: 644

not providedTotal: 130

Inborn genetic diseasesTotal: 60

not specifiedTotal: 58

BIN1-related disorderTotal: 18

Autosomal dominant nonsyndromic hearing loss 22Total: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_139343.3. 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			8 clinvar	148 clinvar	1 clinvar	157
missense	2 clinvar	3 clinvar	292 clinvar	9 clinvar	1 clinvar	307
nonsense	1 clinvar	2 clinvar	5 clinvar			8
start loss						0
frameshift		2 clinvar	6 clinvar			8
splice donor/acceptor (+/-2bp)		5 clinvar	8 clinvar			13
Total	3	12	319	157	2	493

Highest pathogenic variant AF is 0.00001487599

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 250 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_139343.3	RefSeq	NP_647593.1	19	MANE Select
ENST00000316724.10	Ensembl	ENSP00000316779.5	19	MANE Select
NM_001320632.2	RefSeq	NP_001307561.1	14	Standard
NM_001320633.2	RefSeq	NP_001307562.1	15	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
bin1b	Danio rerio	Structure: whole organism Quality: curved abnormal

Gene / Model

Organism

Observed Phenotype

bin1b

Danio rerio

Structure: whole organism

Quality: curved

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fc gamma R-mediated phagocytosis - Homo sapiens (human)
Endocytosis - Homo sapiens (human)
VEGFA-VEGFR2 Signaling Pathway
Vesicle-mediated transport
endocytotic role of ndk phosphins and dynamin

Biological Process

endocytosis
nucleus organization
cytoskeleton organization
cell population proliferation
endosome to lysosome transport

Molecular Function

protease binding
protein binding
phospholipid binding
clathrin binding
identical protein binding

Cellular Component

nucleus
nuclear envelope
cytoplasm
cytosol
cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000316724
Coding exons: 19
Length: 59329
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.25	235	354	0.663	0.0000222	3856
Missense (PolyPhen)		70	123.62	0.56625		1425
Synonymous	0.260	157	161	0.974	0.0000122	1132
Loss of Function	4.46	7	35.8	0.196	0.00000171	394

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in regulation of synaptic vesicle endocytosis. May act as a tumor suppressor and inhibits malignant cell transformation.;
Disease: DISEASE: Myopathy, centronuclear, 2 (CNM2) [MIM:255200]: A congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. {ECO:0000269|PubMed:17676042}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.202

Intolerance Scores

LoFtool: 0.576
RVIS EVS: -0.75
RVIS percentile EVS: 13.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.980

Gene Damage Prediction

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