MGAT2

protein-coding

alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase, the group of Mannosyl-glycoprotein N-acetylglucosaminyltransferases

Gene summary

The product of this gene is a Golgi enzyme catalyzing an essential step in the conversion of oligomannose to complex N-glycans. The enzyme has the typical glycosyltransferase domains: a short N-terminal cytoplasmic domain, a hydrophobic non-cleavable signal-anchor domain, and a C-terminal catalytic domain. Mutations in this gene may lead to carbohydrate-deficient glycoprotein syndrome, type II. The coding region of this gene is intronless. Transcript variants with a spliced 5' UTR may exist, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002408.4

Inheritance

ClinVar variants

P:14U:94B:27

Top phenotype

Congenital disorder of glycosylation, type IIa

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr14:49,620,799-49,623,481

External References & Databases

Ensembl (ENSG00000168282)

Transcript & Mutation Effects

hg38 • Region Span ~2.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

MGAT2-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008908

Submitter: PanelApp Australia

MGAT2-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008908

Submitter: Orphanet

MGAT2-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008908

Submitter: Ambry Genetics

MGAT2-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008908

Submitter: G2P

MGAT2-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008908

Submitter: ClinGen

MGAT2 was first reported in relation to MGAT2-congenital disorder of glycosylation in 1996 (Tan et al., PMID: 8808595). Seven unique variants (missense, nonsense, and frameshift) that have been reported in seven probands in six publications are included in this curation. This gene-disease relationship is also supported by two mouse models – a full gene knockout (Wang et al., PMID: 11805078, Wang et al., PMID:12417412) and a targeted knockout (Ryan et al., PMID: 24310166). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Of the few reports of prenatally diagnosed MGAT2-CDG, hydrops fetalis has been described in one case (PMID: 28742265) and a single case of preterm birth (PMID: 33044030) was separately reported. There is insufficient evidence to establish causation of a prenatal phenotype. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date November 7, 2024 (SOP Version 11).

MGAT2-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008908

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IIaAR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Craniofacial; Gastrointestinal; Hematologic; Musculoskeletal; 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: 7944531; 8808595; 11228641; 19419693; 20684000; 22105986; 23023920

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MGAT2 variants in ClinVar

9 Conditions Cataloged

MGAT2-congenital disorder of glycosylationTotal: 80

Inborn genetic diseasesTotal: 55

not providedTotal: 18

not specifiedTotal: 16

MGAT2-related disorderTotal: 7

Abnormal facial shapeTotal: 1

Abnormal glycosylationTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002408.4. 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			5 clinvar	23 clinvar	2 clinvar	30
missense	3 clinvar	1 clinvar	86 clinvar	2 clinvar		92
nonsense	2 clinvar	2 clinvar				4
start loss						0
frameshift	1 clinvar	5 clinvar	3 clinvar			9
splice donor/acceptor (+/-2bp)						0
Total	6	8	94	25	2	135

Highest pathogenic variant AF is 0.0000037219643

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002408.4	RefSeq	NP_002399.1	1	MANE Select
ENST00000305386.4	Ensembl	ENSP00000307423.2	1	MANE Select
ENST00001120781.1	Ensembl	ENSP00000790586.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

N-Glycan biosynthesis - Homo sapiens (human)
Post-translational protein modification
Reactions specific to the complex N-glycan synthesis pathway
N-glycan antennae elongation in the medial/trans-Golgi
Metabolism of proteins

Biological Process

oligosaccharide biosynthetic process
protein N-linked glycosylation via asparagine

Molecular Function

alpha-1,6-mannosylglycoprotein 2-beta-N-acetylglucosaminyltransferase activity
manganese ion binding
carbohydrate binding
protein homodimerization activity

Cellular Component

Golgi membrane
Golgi apparatus
Golgi stack
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305386
Coding exons: 1
Length: 2710
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	0.515	214	236	0.906	0.0000115	2924
Missense (PolyPhen)		62	87.085	0.71195		1149
Synonymous	-0.398	107	102	1.05	0.00000511	894
Loss of Function	2.34	5	14.7	0.341	7.15e-7	164

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: Catalyzes an essential step in the conversion of oligo- mannose to complex N-glycans.;
Disease: DISEASE: Congenital disorder of glycosylation 2A (CDG2A) [MIM:212066]: A multisystem disorder 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. {ECO:0000269|PubMed:11228641, ECO:0000269|PubMed:8808595}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.122
RVIS EVS: 0.08
RVIS percentile EVS: 60.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.400

Gene Damage Prediction

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