COL4A2

protein-coding

collagen type IV alpha 2 chain, the group of Collagens|MicroRNA protein coding host genes

Gene summary

This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001846.4

Inheritance

ClinVar variants

P:121U:751B:445

Top phenotype

Hemorrhage, intracerebral, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr13:110,305,812-110,513,209

External References & Databases

Ensembl (ENSG00000134871)

Transcript & Mutation Effects

hg38 • Region Span ~207.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial porencephalySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020496

Submitter: Orphanet

COL4A1 or COL4A2-related cerebral small vessel diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0018788

Submitter: Illumina

brain small vessel disease 2A, autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013773

Submitter: Ambry Genetics

brain small vessel disease 2A, autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013773

Submitter: G2P

brain small vessel disease 2A, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013773

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hemorrhage, intracerebral, susceptibility toAD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: The awareness that individuals are at risk for hemorrhagic stroke may allow preventive management related to contributory factors, which may decrease morbidity/mortality.

Comments: Authors have suggested that reported nonglycine variants may result in milder disease later in life or cause disease due to interactions with other factors.

Refs: 22209247; 22209246

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL4A2 variants in ClinVar

26 Conditions Cataloged

not providedTotal: 1339

not specifiedTotal: 266

Brain small vessel disease 2A, autosomal dominantTotal: 261

Inborn genetic diseasesTotal: 250

COL4A2-related disorderTotal: 166

Hemorrhage, intracerebral, susceptibility toTotal: 33

Brain small vessel disease 2B, autosomal recessiveTotal: 7

Intellectual disabilityTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001846.4. 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			9 clinvar	296 clinvar	4 clinvar	309
missense	7 clinvar	40 clinvar	664 clinvar	138 clinvar	6 clinvar	855
nonsense	9 clinvar	7 clinvar	19 clinvar			35
start loss						0
frameshift	18 clinvar	18 clinvar	24 clinvar	1 clinvar		61
splice donor/acceptor (+/-2bp)	2 clinvar	20 clinvar	35 clinvar			57
Total	36	85	751	435	10	1317

Highest pathogenic variant AF is 0.00009676987

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001846.4	RefSeq	NP_001837.2	47	MANE Select
ENST00000360467.7	Ensembl	ENSP00000353654.5	47	MANE Select
ENST00000400163.8	Ensembl	ENSP00000383027.4	47	Standard
ENST00000400163.9	Ensembl	ENSP00000383027.4	47	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Relaxin signaling pathway - Homo sapiens (human)
AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)

Biological Process

angiogenesis
transcription, DNA-templated
aging
response to activity
negative regulation of angiogenesis

Molecular Function

extracellular matrix structural constituent
protein binding
extracellular matrix structural constituent conferring tensile strength

Cellular Component

extracellular region
collagen type IV trimer
extracellular space
endoplasmic reticulum lumen
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360467
Coding exons: 47
Length: 207216
Individuals with no LoFs: 124696
Homozygous LoFs: 0
Heterozygous LoFs: 143
Defined: 124839
p: 0.000573

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.19	842	1.04e+3	0.809	0.0000612	10679
Missense (PolyPhen)		114	267.14	0.42675		2513
Synonymous	0.829	398	420	0.949	0.0000284	3776
Loss of Function	4.81	40	89.0	0.450	0.00000450	1068

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00040	0.00039	rare
Latino/Admixed American	0.00053	0.00049	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00046	0.00044	rare
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.00063	0.00062	rare
South Asian	0.00070	0.00069	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.;
Disease: DISEASE: Porencephaly 2 (POREN2) [MIM:614483]: A neurologic disorder characterized by a fluid-filled cysts or cavities within the cerebral hemispheres. Affected individuals typically have hemiplegia, seizures, and intellectual disability. Porencephaly type 2, or schizencephalic porencephaly, is usually symmetric and represents a primary defect in the development of the cerebral ventricles. {ECO:0000269|PubMed:22209246}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Intracerebral hemorrhage (ICH) [MIM:614519]: A pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke. {ECO:0000269|PubMed:22209247}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.0908
RVIS EVS: -0.64
RVIS percentile EVS: 16.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.540

Gene Damage Prediction

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