FHL2

protein-coding

four and a half LIM domains 2, the group of LIM domain containing

Gene summary

This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. This protein is thought to have a role in the assembly of extracellular membranes. Also, this gene is down-regulated during transformation of normal myoblasts to rhabdomyosarcoma cells and the encoded protein may function as a link between presenilin-2 and an intracellular signaling pathway. Multiple alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2016]

MANE transcript

NM_001318895.3

Inheritance

ClinVar variants

P:1U:160B:60

Top phenotype

familial isolated dilated cardiomyopathy

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr2:105,357,712-105,438,513

External References & Databases

Ensembl (ENSG00000115641)

Transcript & Mutation Effects

hg38 • Region Span ~80.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

cardiomyopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0004994

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FHL2 variants in ClinVar

6 Conditions Cataloged

Primary dilated cardiomyopathyTotal: 225

not specifiedTotal: 66

CardiomyopathyTotal: 15

FHL2-related disorderTotal: 13

not providedTotal: 11

FHL2-related cardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001318895.3. 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			1 clinvar	49 clinvar	4 clinvar	54
missense		1 clinvar	140 clinvar	6 clinvar	1 clinvar	148
nonsense			4 clinvar			4
start loss			2 clinvar			2
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	1	160	55	5	221

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 156 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001318895.3	RefSeq	NP_001305824.1	5	MANE Select
ENST00000530340.6	Ensembl	ENSP00000433567.2	5	MANE Select
NM_001039492.3	RefSeq	NP_001034581.1	5	Standard
NM_001318894.1	RefSeq	NP_001305823.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Osteoclast differentiation - Homo sapiens (human)
Androgen receptor signaling pathway
RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
Ectoderm Differentiation

Biological Process

negative regulation of transcription by RNA polymerase II
osteoblast differentiation
response to hormone
regulation of lipid metabolic process
androgen receptor signaling pathway

Molecular Function

transcription coactivator activity
protein binding
transcription factor binding
identical protein binding
metal ion binding

Cellular Component

nucleus
nucleoplasm
focal adhesion
Z disc
M band

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358129
Coding exons: 5
Length: 80802
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125747
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.899	137	170	0.806	0.00000999	1873
Missense (PolyPhen)		59	76.1	0.77529		843
Synonymous	0.309	59	62.1	0.950	0.00000360	466
Loss of Function	1.22	9	13.9	0.648	5.88e-7	178

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function as a molecular transmitter linking various signaling pathways to transcriptional regulation. Negatively regulates the transcriptional repressor E4F1 and may function in cell growth. Inhibits the transcriptional activity of FOXO1 and its apoptotic function by enhancing the interaction of FOXO1 with SIRT1 and FOXO1 deacetylation. Negatively regulates the calcineurin/NFAT signaling pathway in cardiomyocytes (PubMed:28717008). {ECO:0000269|PubMed:15692560, ECO:0000269|PubMed:16652157, ECO:0000269|PubMed:18853468, ECO:0000269|PubMed:28717008}.;

Recessive Scores

pRec: 0.435

Intolerance Scores

LoFtool: 0.0595
RVIS EVS: 0.31
RVIS percentile EVS: 72.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.930

Gene Damage Prediction

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