COG2

protein-coding

component of oligomeric golgi complex 2, the group of Components of oligomeric golgi complex

Gene summary

This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi complex. The encoded protein specifically interacts with the USO1 vesicle docking protein and may be necessary for normal Golgi ribbon formation and trafficking of Golgi enzymes. Mutations of this gene are associated with abnormal glycosylation within the Golgi apparatus. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

Previous symbols:

LDLC

MANE transcript

NM_007357.3

Inheritance

ClinVar variants

P:6U:134B:69

Top phenotype

Congenital disorder of glycosylation, type IIq

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr1:230,642,481-230,693,982

External References & Databases

Ensembl (ENSG00000135775)

Transcript & Mutation Effects

hg38 • Region Span ~51.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital disorder of glycosylation, type IIqSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054559

Submitter: Orphanet

congenital disorder of glycosylation, type IIqLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0054559

Submitter: ClinGen

***COG2*** was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Kodera H et al. in 2015 (PMID: 24784932). ***COG2*** has only been reported in one additional proband since the first publication. Mutations in ***COG2*** can lead to Congenital disorder of glycosylation (CDG), type IIq. CDGs result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor delay, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. Clinical features of CDG-II caused by ***COG2*** are characterized by normal presentation at birth, followed by progressive deterioration with postnatal microcephaly, developmental delay, intellectual disability, seizures, spastic quadriplegia, liver dysfunction, hypocupremia and hypoceruloplasminemia in the first year of life. No supporting segregation information is available, and the disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is supported by the biochemical function of ***COG2***, the protein encoded by this gene is one of eight proteins (Cog1-8) that form a Golgi-localized complex (COG) required for normal Golgi morphology and function. LDLC CHO cells have shown the effects of **COG2** and its restoration capabilities when transfected in the CHO cells (PMID: 21047787, 7962052). Coimmunoprecipitation experiments showed interaction with other proteins in the COG complex, specifically its interaction with ***COG1***, ***COG3***, and ***COG5***(PMID: 11980916). Although additional genetic and experimental evidence is needed to establish a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. A classification of LIMITED was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 2/7/24 (SOP Version 10)

congenital disorder of glycosylation, type IIqSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054559

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IIqAR

Manifestation: Biochemical; Gastrointestinal; Hematologic; Neurologic

Intervention: Hematologic

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 24784932

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COG2 variants in ClinVar

5 Conditions Cataloged

Congenital disorder of glycosylation, type IIqTotal: 139

not specifiedTotal: 104

not providedTotal: 33

COG2-related disorderTotal: 9

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007357.3. 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			5 clinvar	51 clinvar	7 clinvar	63
missense			124 clinvar	11 clinvar		135
nonsense		2 clinvar	2 clinvar			4
start loss						0
frameshift	4 clinvar		2 clinvar			6
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	4	2	134	62	7	209

Highest pathogenic variant AF is 0.000006819371

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007357.3	RefSeq	NP_031383.1	18	MANE Select
ENST00000366669.9	Ensembl	ENSP00000355629.4	18	MANE Select
NM_001145036.2	RefSeq	NP_001138508.1	18	Standard
ENST00000366668.7	Ensembl	ENSP00000355628.3	18	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
Transport to the Golgi and subsequent modification

Biological Process

endoplasmic reticulum to Golgi vesicle-mediated transport
intra-Golgi vesicle-mediated transport
Golgi organization
protein transport

Molecular Function

protein binding
protein transporter activity
protein-containing complex binding

Cellular Component

Golgi membrane
Golgi stack
cytosol
Golgi transport complex
trans-Golgi network membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366669
Coding exons: 18
Length: 51494
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125748
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.854	351	399	0.880	0.0000214	4830
Missense (PolyPhen)		86	121.45	0.70808		1499
Synonymous	-1.04	168	152	1.11	0.00000886	1396
Loss of Function	3.63	16	41.1	0.389	0.00000219	501

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000091	0.000087	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.00010	0.000098	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for normal Golgi morphology and function.;
Disease: DISEASE: Congenital disorder of glycosylation 2Q (CDG2Q) [MIM:617395]: A form of congenital disorder of glycosylation, a genetically heterogeneous group of autosomal recessive, multisystem disorders caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The transmission pattern of CDG2Q is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:24784932}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.251

Intolerance Scores

LoFtool: 0.832
RVIS EVS: -0.33
RVIS percentile EVS: 30.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.822

Gene Damage Prediction

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