MFN2

mitofusin 2

Basic information

Region (hg38): 1:11980180-12015211

Links

ENSG00000116688 ∙ NCBI:9927 ∙ OMIM:608507 ∙ HGNC:16877 ∙ Uniprot:O95140 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• multiple symmetric lipomatosis (Supportive), mode of inheritance: AD
• severe early-onset axonal neuropathy due to MFN2 deficiency (Supportive), mode of inheritance: AR
• hereditary motor and sensory neuropathy type 6 (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 2A2 (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 2A2 (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (Strong), mode of inheritance: AR
• axonal hereditary motor and sensory neuropathy (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lipomatosis, multiple symmetric, with or without peripheral neuropathy	AR	Dermatologic	The severity of manifestations in Lipomatosis, multiple symmetric, with or without peripheral neuropathy has been suggested as being influenced by alcohol consumption	Dermatologic; Neurologic; Ophthalmologic	9409358; 11148244; 11850759; 12601114; 15136675; 15064763; 16043786; 16087932; 16835246; 16437557; 17309650; 18458227; 18946002; 20008656; 19889647; 21715711; 22206013; 22526351; 22546700; 22653593; 22762946; 22957060; 26085578; 28414270; 30649465

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MFN2 gene.

• Charcot-Marie-Tooth disease type 2 (922 variants)
• not provided (294 variants)
• Charcot-Marie-Tooth disease (165 variants)
• Inborn genetic diseases (132 variants)
• Hereditary motor and sensory neuropathy with optic atrophy (110 variants)
• not specified (85 variants)
• Charcot-Marie-Tooth disease type 2A2 (68 variants)
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (20 variants)
• Hereditary motor and sensory neuropathy (13 variants)
• Neuropathy, hereditary motor and sensory, type 6A (9 variants)
• MFN2-related condition (6 variants)
• Tip-toe gait (3 variants)
• Peripheral neuropathy (3 variants)
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;Neuropathy, hereditary motor and sensory, type 6A;Charcot-Marie-Tooth disease type 2A2 (3 variants)
• Charcot-Marie-Tooth disease type 4 (3 variants)
• MFN2-Related Disorders (2 variants)
• Charcot-Marie-Tooth disease type 2A2;Neuropathy, hereditary motor and sensory, type 6A (2 variants)
• Ehlers-Danlos syndrome, kyphoscoliotic type 1 (2 variants)
• Charcot-Marie-Tooth disease type 2A2;Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;Neuropathy, hereditary motor and sensory, type 6A (2 variants)
• Cerebral palsy (1 variants)
• Hereditary motor and sensory neuropathy with optic atrophy;Charcot-Marie-Tooth disease, type 2A (1 variants)
• Global developmental delay (1 variants)
• Auditory neuropathy (1 variants)
• Severe early-onset axonal neuropathy due to MFN2 deficiency (1 variants)
• Neuropathy, hereditary motor and sensory, type 6A;Charcot-Marie-Tooth disease type 2A2;Charcot-Marie-Tooth disease type 2A1;Charcot-Marie-Tooth disease, type 2A;Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (1 variants)
• Distal lower limb amyotrophy;Peripheral axonal neuropathy;Distal muscle weakness (1 variants)
• Neuropathy, hereditary motor and sensory, type 6A;Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;Charcot-Marie-Tooth disease type 2A2 (1 variants)
• 14 conditions (1 variants)
• Multiple symmetric lipomatosis;Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (1 variants)
• Peripheral axonal neuropathy (1 variants)
• Charcot-Marie-Tooth disease type 2A2;Hereditary motor and sensory neuropathy with optic atrophy;Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (1 variants)
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;Hereditary motor and sensory neuropathy with optic atrophy;Charcot-Marie-Tooth disease type 2A2 (1 variants)
• Hereditary motor neuron disease (1 variants)
• Hereditary motor and sensory neuropathy with optic atrophy;Charcot-Marie-Tooth disease type 2A2;Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (1 variants)
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;Charcot-Marie-Tooth disease type 2A2;Neuropathy, hereditary motor and sensory, type 6A (1 variants)
• Charcot-Marie-Tooth disease, type 2A (1 variants)
• Cerebellar ataxia (1 variants)
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;Charcot-Marie-Tooth disease type 2A2;Hereditary motor and sensory neuropathy with optic atrophy (1 variants)
• Multiple system atrophy, cerebellar type (1 variants)
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;;Charcot-Marie-Tooth disease type 2A2 (1 variants)
• Multiple symmetric lipomatosis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MFN2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	160	5	171
missense	44	68	432	7		551
nonsense	19	4	2			25
start loss			1			1
frameshift	13	3	2			18
inframe indel			17			17
splice donor/acceptor (+/-2bp)	4	7	1			12
splice region			25	28		53
non coding	1	1	38	114	65	219
Total	81	83	499	281	70

Highest pathogenic variant AF is 0.0000461

Variants in MFN2

This is a list of pathogenic ClinVar variants found in the MFN2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-11980252-G-A		Charcot-Marie-Tooth disease type 2 • Hereditary motor and sensory neuropathy with optic atrophy	Uncertain significance (Jan 13, 2018)
1-11980267-A-G		Hereditary motor and sensory neuropathy • Ehlers-Danlos syndrome, kyphoscoliotic type 1 • Charcot-Marie-Tooth disease type 2 • Hereditary motor and sensory neuropathy with optic atrophy	Benign (Jun 29, 2018)
1-11980275-C-G		Hereditary motor and sensory neuropathy with optic atrophy • Charcot-Marie-Tooth disease type 2	Uncertain significance (Jan 13, 2018)
1-11980290-C-T		Hereditary motor and sensory neuropathy with optic atrophy • Charcot-Marie-Tooth disease type 2	Uncertain significance (Jan 13, 2018)
1-11980306-T-A		Hereditary motor and sensory neuropathy with optic atrophy • Charcot-Marie-Tooth disease type 2	Uncertain significance (Jan 13, 2018)
1-11980347-C-T		Charcot-Marie-Tooth disease type 2 • Hereditary motor and sensory neuropathy • Hereditary motor and sensory neuropathy with optic atrophy	Benign/Likely benign (Dec 21, 2021)
1-11980385-T-A		Charcot-Marie-Tooth disease type 2 • Hereditary motor and sensory neuropathy • Hereditary motor and sensory neuropathy with optic atrophy	Benign/Likely benign (Dec 21, 2021)
1-11980417-C-A		Hereditary motor and sensory neuropathy with optic atrophy • Charcot-Marie-Tooth disease type 2	Uncertain significance (Jan 13, 2018)
1-11980422-T-C		Hereditary motor and sensory neuropathy • Charcot-Marie-Tooth disease type 2 • Ehlers-Danlos syndrome, kyphoscoliotic type 1 • Hereditary motor and sensory neuropathy with optic atrophy	Benign (Jun 29, 2018)
1-11980473-G-A		Charcot-Marie-Tooth disease type 2 • Hereditary motor and sensory neuropathy with optic atrophy • not specified	Benign/Likely benign (Jan 13, 2018)
1-11980488-A-T			Uncertain significance (Aug 28, 2015)
1-11980503-C-T		not specified	Likely benign (Aug 23, 2016)
1-11980504-G-A		not specified	Likely benign (Oct 04, 2016)
1-11981920-G-GTTTTTT			Benign (Feb 21, 2020)
1-11981920-G-GTTTTTTT			Benign (Oct 23, 2019)
1-11981920-G-GTTTTTTTT			Benign (Oct 23, 2019)
1-11981920-G-GTTTTGTTTTT			Likely benign (Dec 01, 2021)
1-11981950-C-A		not specified	Likely benign (Mar 03, 2017)
1-11981955-T-G		not specified • Charcot-Marie-Tooth disease type 2 • Hereditary motor and sensory neuropathy with optic atrophy	Benign/Likely benign (Apr 27, 2017)
1-11982039-C-T		Hereditary motor and sensory neuropathy with optic atrophy • Charcot-Marie-Tooth disease type 2	Benign (Jan 13, 2018)
1-11982109-A-G		not specified	Likely benign (Aug 07, 2017)
1-11982204-A-G			Benign (Jun 29, 2018)
1-11982241-C-T			Benign (Jun 29, 2018)
1-11988944-C-A			Likely benign (Oct 21, 2018)
1-11989152-G-T		Charcot-Marie-Tooth disease type 2 • Hereditary motor and sensory neuropathy with optic atrophy • Charcot-Marie-Tooth disease	Benign/Likely benign (Apr 13, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MFN2	protein_coding	protein_coding	ENST00000235329	17	33334

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.994	0.00585	125729	0	19	125748	0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.66	326	422	0.773	0.0000274	5025
Missense in Polyphen		117	170.71	0.68538		2146
Synonymous	-0.534	172	163	1.05	0.0000103	1456
Loss of Function	4.90	5	37.3	0.134	0.00000206	421

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000213	0.000152
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000109	0.000109
Finnish	0.0000467	0.0000462
European (Non-Finnish)	0.0000799	0.0000791
Middle Eastern	0.000109	0.000109
South Asian	0.0000653	0.0000653
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion (PubMed:11181170, PubMed:11950885, PubMed:28114303). Mitochondria are highly dynamic organelles, and their morphology is determined by the equilibrium between mitochondrial fusion and fission events (PubMed:28114303). Overexpression induces the formation of mitochondrial networks (PubMed:28114303). Membrane clustering requires GTPase activity and may involve a major rearrangement of the coiled coil domains (Probable). Plays a central role in mitochondrial metabolism and may be associated with obesity and/or apoptosis processes (By similarity). Plays an important role in the regulation of vascular smooth muscle cell proliferation (By similarity). Involved in the clearance of damaged mitochondria via selective autophagy (mitophagy) (PubMed:23620051). Is required for PRKN recruitment to dysfunctional mitochondria (PubMed:23620051). Involved in the control of unfolded protein response (UPR) upon ER stress including activation of apoptosis and autophagy during ER stress (By similarity). Acts as an upstream regulator of EIF2AK3 and suppresses EIF2AK3 activation under basal conditions (By similarity). {ECO:0000250|UniProtKB:Q80U63, ECO:0000250|UniProtKB:Q8R500, ECO:0000269|PubMed:11181170, ECO:0000269|PubMed:11950885, ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:26085578, ECO:0000269|PubMed:28114303, ECO:0000305}.
• Disease: DISEASE: Charcot-Marie-Tooth disease 2A2B (CMT2A2B) [MIM:617087]: An axonal 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. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2A2B is a severe form with autosomal recessive inheritance. {ECO:0000269|PubMed:18458227, ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:21715711, ECO:0000269|PubMed:26085578, ECO:0000269|PubMed:26955893}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2A2A (CMT2A2A) [MIM:609260]: An axonal 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. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:15064763, ECO:0000269|PubMed:15549395, ECO:0000269|PubMed:16762064, ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:22206013}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neuropathy, hereditary motor and sensory, 6A (HMSN6A) [MIM:601152]: An autosomal dominant neurologic disorder characterized by optic atrophy and peripheral sensorimotor neuropathy manifesting as axonal Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease is 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. It is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies and primary peripheral axonal neuropathies. Peripheral axonal neuropathies are characterized by signs of axonal regeneration in the absence of obvious myelin alterations, and normal or slightly reduced nerve conduction velocities. {ECO:0000269|PubMed:16437557, ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:24604904, ECO:0000269|PubMed:26085578}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mitophagy - animal - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Factors involved in megakaryocyte development and platelet production;Pink/Parkin Mediated Mitophagy;Mitophagy;Hemostasis (Consensus)

Recessive Scores

• pRec: 0.0922

Intolerance Scores

• loftool: 0.0178
• rvis_EVS: -0.77
• rvis_percentile_EVS: 13.1

Haploinsufficiency Scores

• pHI: 0.0839
• hipred: Y
• hipred_score: 0.704
• ghis: 0.576

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.992

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mfn2
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; growth/size/body region phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; pigmentation phenotype; embryo phenotype

Zebrafish Information Network

• Gene name: mfn2
• Affected structure: thrombocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: blastocyst formation;protein targeting to mitochondrion;apoptotic process;response to unfolded protein;mitochondrial membrane organization;cell cycle arrest;blood coagulation;mitochondrial fusion;macroautophagy;protein localization to phagophore assembly site;negative regulation of Ras protein signal transduction;camera-type eye morphogenesis;negative regulation of smooth muscle cell proliferation;mitochondrion localization;parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization;positive regulation of cold-induced thermogenesis;positive regulation of vascular smooth muscle cell proliferation;positive regulation of vascular associated smooth muscle cell apoptotic process
• Cellular component: mitochondrion;mitochondrial outer membrane;cytosol;microtubule cytoskeleton;integral component of membrane;intrinsic component of mitochondrial outer membrane
• Molecular function: GTPase activity;protein binding;GTP binding;ubiquitin protein ligase binding