CFC1

protein-coding

cripto, FRL-1, cryptic family 1

Gene summary

This gene encodes a member of the epidermal growth factor (EGF)- Cripto, Frl-1, and Cryptic (CFC) family, which are involved in signalling during embryonic development. Proteins in this family share a variant EGF-like motif, a conserved cysteine-rich domain, and a C-terminal hydrophobic region. The protein encoded by this gene is necessary for patterning the left-right embryonic axis. Mutations in this gene are associated with defects in organ development, including autosomal visceral heterotaxy and congenital heart disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

Previous symbols:

HTX2

MANE transcript

NM_032545.4

Inheritance

ClinVar variants

P:2U:26B:19

Top phenotype

Heterotaxy, visceral, 2, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr2:130,592,165-130,599,575

External References & Databases

Ensembl (ENSG00000136698)

Transcript & Mutation Effects

hg38 • Region Span ~7.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

heterotaxy, visceral, 2, autosomalSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011546

Submitter: Labcorp Genetics (formerly Invitae)

heterotaxy, visceral, 2, autosomalLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011546

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Heterotaxy, visceral, 2, autosomal dominantAD

Manifestation: Cardiovascular; Gastrointestinal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 11062482; 11562933; 11799476; 18538293

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CFC1 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 22

Inborn genetic diseasesTotal: 16

not specifiedTotal: 12

Heterotaxy, visceral, 2, autosomalTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032545.4. 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			1 clinvar	5 clinvar	4 clinvar	10
missense	1 clinvar		19 clinvar	5 clinvar	4 clinvar	29
nonsense						0
start loss						0
frameshift		1 clinvar	6 clinvar	1 clinvar		8
splice donor/acceptor (+/-2bp)						0
Total	1	1	26	11	8	47

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032545.4	RefSeq	NP_115934.1	6	MANE Select
ENST00000259216.6	Ensembl	ENSP00000259216.5	6	MANE Select
NM_001270420.2	RefSeq	NP_001257349.1	5	Standard
NM_001270421.2	RefSeq	NP_001257350.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Developmental Biology
Regulation of signaling by NODAL
Signaling by NODAL

Biological Process

determination of left/right symmetry
gastrulation
heart development
anterior/posterior pattern specification
BMP signaling pathway

Molecular Function

molecular_function
signaling receptor binding
nodal binding
activin receptor binding

Cellular Component

cellular_component
extracellular region
plasma membrane
cell surface
anchored component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000259216
Coding exons: 6
Length: 6785
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.224	43	39.1	1.10	0.00000211	1370
Missense (PolyPhen)		2	2.3308	0.85806		358
Synonymous	-0.837	25	20.2	1.24	0.00000148	447
Loss of Function	1.24	2	4.99	0.401	2.64e-7	114

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: NODAL coreceptor involved in the correct establishment of the left-right axis. May play a role in mesoderm and/or neural patterning during gastrulation. {ECO:0000269|PubMed:11062482}.;
Disease: DISEASE: Heterotaxy, visceral, 2, autosomal (HTX2) [MIM:605376]: A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can been associated with variety of congenital defects including cardiac malformations. {ECO:0000269|PubMed:11062482, ECO:0000269|PubMed:11799476}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.128

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.147

Gene Damage Prediction

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