CFL2

protein-coding

cofilin 2

Gene summary

This gene encodes an intracellular protein that is involved in the regulation of actin-filament dynamics. This protein is a major component of intranuclear and cytoplasmic actin rods. It can bind G- and F-actin in a 1:1 ratio of cofilin to actin, and it reversibly controls actin polymerization and depolymerization in a pH-dependent manner. Mutations in this gene cause nemaline myopathy type 7, a form of congenital myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

MANE transcript

NM_138638.5

Inheritance

AR, AD

ClinVar variants

P:7U:55B:19

Top phenotype

Nemaline myopathy 7

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr14:34,709,113-34,714,823

External References & Databases

Ensembl (ENSG00000165410)

Transcript & Mutation Effects

hg38 • Region Span ~5.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nemaline myopathy 7MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012538

Submitter: Ambry Genetics

nemaline myopathy 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012538

Submitter: ClinGen

CFL2 was first reported in relation to autosomal recessive nemaline myopathy 7 in 2007 (Agrawal PB, et al., 2007, PMID: 17160903). At least 9 unique variants (e.g. missense, nonsense, and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 7 probands in six publications (PMIDs: 17160903, 22560515, 29457652, 24610938, 27848944, 27447704). Variants in this gene segregated with disease in 3 additional family members. This gene-disease relationship is supported by its biochemical function in actin-filament dynamics (PMID: 26996939), its expression in skeletal muscle (PMID: 11422377), and at least two knockout mouse models (PMIDs: 22343409, 2459838). In summary, there is strong evidence to support the relationship between CFL2 and autosomal recessive nemaline myopathy 7.

nemaline myopathy 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012538

Submitter: Labcorp Genetics (formerly Invitae)

typical nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015737

Submitter: Orphanet

nemaline myopathy 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012538

Submitter: G2P

Clinical Genomic Database (CGD)

Nemaline myopathy 7AR

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: 17160903

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CFL2 variants in ClinVar

7 Conditions Cataloged

Nemaline myopathy 7Total: 97

not providedTotal: 17

not specifiedTotal: 7

Inborn genetic diseasesTotal: 7

CFL2-related disorderTotal: 3

Centronuclear myopathyTotal: 1

Muscle weaknessTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138638.5. 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			1 clinvar	19 clinvar		20
missense	1 clinvar	1 clinvar	52 clinvar			54
nonsense		1 clinvar				1
start loss						0
frameshift	3 clinvar	1 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	4	3	55	19	0	81

Highest pathogenic variant AF is 0.000008059017

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138638.5	RefSeq	NP_619579.1	4	MANE Select
ENST00000298159.11	Ensembl	ENSP00000298159.6	4	MANE Select
NM_001243645.2	RefSeq	NP_001230574.1	3	Standard
NM_021914.8	RefSeq	NP_068733.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fc gamma R-mediated phagocytosis - Homo sapiens (human)
Pertussis - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)
Axon guidance - Homo sapiens (human)
Leptin signaling pathway

Biological Process

skeletal muscle tissue development
actin filament depolymerization
actin filament fragmentation
positive regulation of actin filament depolymerization
sarcomere organization

Molecular Function

protein binding
actin filament binding

Cellular Component

extracellular space
actin cytoskeleton
nuclear matrix
Z disc
I band

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000341223
Coding exons: 4
Length: 4437
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125740
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.61	43	84.8	0.507	0.00000411	1090
Missense (PolyPhen)		6	15.462	0.38804		225
Synonymous	1.14	23	31.1	0.740	0.00000169	298
Loss of Function	0.472	7	8.48	0.825	4.44e-7	103

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Controls reversibly actin polymerization and depolymerization in a pH-sensitive manner. Its F-actin depolymerization activity is regulated by association with CSPR3 (PubMed:19752190). It has the ability to bind G- and F-actin in a 1:1 ratio of cofilin to actin. It is the major component of intranuclear and cytoplasmic actin rods. Required for muscle maintenance. May play a role during the exchange of alpha-actin forms during the early postnatal remodeling of the sarcomere (By similarity). {ECO:0000250|UniProtKB:P45591, ECO:0000269|PubMed:19752190}.;
Disease: DISEASE: Nemaline myopathy 7 (NEM7) [MIM:610687]: A form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. Nemaline myopathy type 7 presents at birth with hypotonia and generalized weakness. Major motor milestones are delayed, but independent ambulation is achieved. {ECO:0000269|PubMed:17160903, ECO:0000269|PubMed:22560515}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.171

Intolerance Scores

LoFtool: 0.563
RVIS EVS: 0.01
RVIS percentile EVS: 54.63

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.941

Gene Damage Prediction

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