MCFD2

protein-coding

multiple coagulation factor deficiency 2, ER cargo receptor complex subunit, the group of EF-hand domain containing

Gene summary

This gene encodes a soluble luminal protein with two calmodulin-like EF-hand motifs at its C-terminus. This protein forms a complex with LMAN1 (lectin mannose binding protein 1; also known as ERGIC-53) that facilitates the transport of coagulation factors V (FV) and VIII (FVIII) from the endoplasmic reticulum to the Golgi apparatus via an endoplasmic reticulum Golgi intermediate compartment (ERGIC). Mutations in this gene cause combined deficiency of FV and FVIII (F5F8D); a rare autosomal recessive bleeding disorder characterized by mild to moderate bleeding and coordinate reduction in plasma FV and FVIII levels. This protein has also been shown to maintain stem cell potential in adult central nervous system and is a marker for testicular germ cell tumors. The 3' UTR of this gene contains a transposon-like human repeat element named 'THE 1'. A processed RNA pseudogene of this gene is on chromosome 6p22.1. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2016]

MANE transcript

NM_139279.6

Inheritance

ClinVar variants

P:11U:40B:2

Top phenotype

Factor V and Factor VIII, combined deficiency of, 2

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr2:46,901,870-46,941,855

External References & Databases

Ensembl (ENSG00000180398)

Transcript & Mutation Effects

hg38 • Region Span ~40.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

factor 5 and Factor VIII, combined deficiency of, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013331

Submitter: Genomics England PanelApp

factor 5 and Factor VIII, combined deficiency of, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013331

Submitter: Ambry Genetics

factor 5 and Factor VIII, combined deficiency of, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013331

Submitter: ClinGen

MCFD2 was first reported in relation to autosomal recessive factor V and factor VIII, combined deficiency in 2003 (Zhang B, et al., 2003, PMID: 12717434). At least 21 unique variants (including missense, nonsense, frameshift, and splicing) 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 9 probands in 2 publications (PMIDs: 12717434, 17610559). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene disease association is supported by its biochemical function as a cargo receptor for the ER-to-Golgi transport of factor V and factor VIII ( PMID: 15886209), its interaction with LMAN1 (PMID: 12717434) which is also implicated in this disease, and a knockout mouse model (PMID: 29735583) that also exhibits reductions of both factor V and factor VIII. In summary, MCFD2 is definitively associated with autosomal recessive inheritance of factor V and factor VIII, combined deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

factor 5 and Factor VIII, combined deficiency of, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013331

Submitter: PanelApp Australia

factor 5 and Factor VIII, combined deficiency of, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013331

Submitter: Labcorp Genetics (formerly Invitae)

combined deficiency of factor V and factor VIIISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018175

Submitter: Orphanet

Clinical Genomic Database (CGD)

Factor V and Factor VIII, combined deficiency of, 2AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Preventive measures and prompt treatment of bleeding diathese may reduce morbidity; Medical treatment to replace absent factors can be effective (eg, with FFP for FV, Desmopression or FVIII concentrates/recombinant products/plasma-derived factor for FVIII)

Refs: 12717434; 15333032; 16304051; 19141160; 18391077; 21492322; 22535353

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MCFD2 variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 33

Factor 5 and Factor VIII, combined deficiency of, 2Total: 18

not providedTotal: 7

MCFD2-related disorderTotal: 3

ThrombocytopeniaTotal: 2

Factor V and factor VIII, combined deficiency of, type 1Total: 2

Abnormal bleedingTotal: 2

Reduced von Willebrand factor activityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_139279.6. 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			3 clinvar	1 clinvar		4
missense	3 clinvar	2 clinvar	35 clinvar	1 clinvar		41
nonsense						0
start loss						0
frameshift	2 clinvar	2 clinvar				4
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	2 clinvar			4
Total	6	5	40	2	0	53

Highest pathogenic variant AF is 0.000017967113

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_139279.6	RefSeq	NP_644808.1	3	MANE Select
ENST00000319466.9	Ensembl	ENSP00000317271.4	3	MANE Select
NM_001171506.2	RefSeq	NP_001164977.1	3	Standard
NM_001171507.2	RefSeq	NP_001164978.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification
Metabolism of proteins
Cargo concentration in the ER

Biological Process

endoplasmic reticulum to Golgi vesicle-mediated transport
protein transport
COPII vesicle coating

Molecular Function

calcium ion binding
protein binding

Cellular Component

Golgi membrane
endoplasmic reticulum membrane
ER to Golgi transport vesicle membrane
endoplasmic reticulum-Golgi intermediate compartment membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409105
Coding exons: 3
Length: 39986
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125747
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.575	91	76.8	1.18	0.00000378	978
Missense (PolyPhen)		15	17.979	0.8343		275
Synonymous	-0.519	36	32.2	1.12	0.00000188	267
Loss of Function	1.21	2	4.87	0.411	2.10e-7	64

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
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)	0.000026	0.000026	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins. Plays a role in the secretion of coagulation factors. {ECO:0000269|PubMed:12717434}.;
Disease: DISEASE: Factor V and factor VIII combined deficiency 2 (F5F8D2) [MIM:613625]: A blood coagulation disorder characterized by bleeding symptoms similar to those in hemophilia or parahemophilia, that are caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma levels of coagulation factors V and VIII are in the range of 5 to 30% of normal. {ECO:0000269|PubMed:12717434, ECO:0000269|PubMed:18590741, ECO:0000269|PubMed:18685427, ECO:0000269|PubMed:20491958}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.0726
RVIS EVS: -0.16
RVIS percentile EVS: 41.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.903

Gene Damage Prediction

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