INF2

protein-coding

inverted formin 2, the group of Formins|Armadillo like helical domain containing

Gene summary

This gene represents a member of the formin family of proteins. It is considered a diaphanous formin due to the presence of a diaphanous inhibitory domain located at the N-terminus of the encoded protein. Studies of a similar mouse protein indicate that the protein encoded by this locus may function in polymerization and depolymerization of actin filaments. Mutations at this locus have been associated with focal segmental glomerulosclerosis 5.[provided by RefSeq, Aug 2010]

Previous symbols:

C14orf151
C14orf173

MANE transcript

NM_022489.4

Inheritance

ClinVar variants

P:67U:628B:717

Top phenotype

Focal segmental glomerulosclerosis 5

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr14:104,681,146-104,722,535

External References & Databases

Ensembl (ENSG00000203485)

Transcript & Mutation Effects

hg38 • Region Span ~41.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

focal segmental glomerulosclerosis 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013191

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease dominant intermediate EDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013758

Submitter: ClinGen

In the context of an autosomal dominant, intermediate Charcot-Marie-Tooth (CMT) phenotype and concomitant focal segmental glomerulosclerosis (FSGS), INF2 was first described by Boyer and colleagues in a series of 12 families in 2011 (PMID: 22187985). To date, 25 missense mutations and 3 in-frame deletions, all clustering in the diaphanous inhibitory domain (DID), have been associated with neuropathy (PMIDs e.g.: 24174593, 24487800, 24750328, 25676889). De-novo mutations are common, and the disease phenotype is highly specific with always including a progressive nephrotic syndrome, sometimes even preceding the neuropathy diagnosis by several years. INF2 encodes a member of the diaphanous-related formin family, which is involved in remodeling of the actin cytoskeleton, in mitochondrial dynamics, and microtubule stabilization. It is expressed in human sural nerves (PMID: 22187985) and co-localizes with the myelin protein MAL (PMID: 22187985). In mouse Schwann and HeLa cells, different mutants resulted in a disturbed actin-INF2-colocalization in the perinuclear area, and in patient sural nerve specimens, filamentous actin accumulated in the intracellular space (PMID: 22187985). A constitutive activation of the DID domain resulted in a reduction of mitochondrial length in transfected U2OS cells (PMID: 23349293). Morpholino-knockdown of INF2 in zebrafish resulted in a dorsalized and curling gross phenotype, which was partially rescued by co-injection of human wildtype INF2, but not by several mutants (PMID: 26086034). In summary, strong clinical evidence, including a highly specific phenotype, the de-novo occurrence of co-segregating variants, and the absence of such variants in healthy control collectives, is supported by experimental data on gene and variant level and has been replicated over time. We therefore classify the gene-disease relationship of INF2 and autosomal dominant, intermediate CMT with FSGS as definitive.

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

Charcot-Marie-Tooth disease dominant intermediate ESUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013758

Submitter: Orphanet

focal segmental glomerulosclerosis 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013191

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease dominant intermediate ESTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013758

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease dominant intermediate ESTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013758

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Focal segmental glomerulosclerosis 5AD

Manifestation: Neurologic; Renal

Intervention: Renal

Rationale: The condition can involve renal failure, and early diagnosis may enable management considerations

Refs: 20023659; 21415313; 22187985; 22961558; 22971997

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to INF2 variants in ClinVar

28 Conditions Cataloged

Focal segmental glomerulosclerosis 5Total: 1509

Charcot-Marie-Tooth disease dominant intermediate ETotal: 1479

not providedTotal: 372

Inborn genetic diseasesTotal: 271

not specifiedTotal: 203

INF2-related disorderTotal: 193

Focal segmental glomerulosclerosisTotal: 16

Charcot-Marie-Tooth diseaseTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022489.4. 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			15 clinvar	437 clinvar	18 clinvar	470
missense	15 clinvar	48 clinvar	562 clinvar	238 clinvar	22 clinvar	885
nonsense			14 clinvar			14
start loss						0
frameshift		3 clinvar	25 clinvar	2 clinvar		30
splice donor/acceptor (+/-2bp)		1 clinvar	12 clinvar			13
Total	15	52	628	677	40	1412

Highest pathogenic variant AF is 0.0000041096564

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022489.4	RefSeq	NP_071934.3	21	MANE Select
ENST00000392634.9	Ensembl	ENSP00000376410.4	21	MANE Select
NM_001031714.4	RefSeq	NP_001026884.3	21	Standard
NM_001426862.1	RefSeq	NP_001413791.1	22	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
inf2	Danio rerio	Structure: glomerular basement membrane Quality: increased permeability abnormal

Gene / Model

Organism

Observed Phenotype

inf2

Danio rerio

Structure: glomerular basement membrane

Quality: increased permeability

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary Focal Segmental Glomerulosclerosis FSGS

Biological Process

actin cytoskeleton organization
regulation of mitochondrial fission

Molecular Function

actin binding
Rho GTPase binding

Cellular Component

perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392634
Coding exons: 21
Length: 30000
Individuals with no LoFs: 124713
Homozygous LoFs: 0
Heterozygous LoFs: 57
Defined: 124770
p: 0.000228

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.31	581	760	0.764	0.0000515	7893
Missense (PolyPhen)		75	159.9	0.46904		1675
Synonymous	-0.457	375	364	1.03	0.0000276	2660
Loss of Function	5.64	10	55.3	0.181	0.00000300	578

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00032	rare
Latino/Admixed American	0.00028	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00067	0.00067	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.000065	0.000065	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Severs actin filaments and accelerates their polymerization and depolymerization. {ECO:0000250}.;
Disease: DISEASE: Focal segmental glomerulosclerosis 5 (FSGS5) [MIM:613237]: A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. {ECO:0000269|PubMed:20023659, ECO:0000269|PubMed:21258034, ECO:0000269|PubMed:21866090, ECO:0000269|PubMed:22971997, ECO:0000269|PubMed:23014460, ECO:0000269|PubMed:25165188}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, dominant, intermediate type, E (CMTDIE) [MIM:614455]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. The dominant intermediate type E is characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. Patients additionally manifest focal segmental glomerulonephritis, proteinuria, progression to end- stage renal disease, and a characteristic histologic pattern on renal biopsy. {ECO:0000269|PubMed:22187985, ECO:0000269|PubMed:24174593, ECO:0000269|PubMed:24750328, ECO:0000269|PubMed:25165188, ECO:0000269|PubMed:25676889}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.0417
RVIS EVS: -0.03
RVIS percentile EVS: 50.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.252

Gene Damage Prediction

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