GANAB

protein-coding

glucosidase II alpha subunit, the group of Glycoside hydrolase family 31

Gene summary

This gene encodes the alpha subunit of glucosidase II and a member of the glycosyl hydrolase 31 family of proteins. The heterodimeric enzyme glucosidase II plays a role in protein folding and quality control by cleaving glucose residues from immature glycoproteins in the endoplasmic reticulum. Expression of the encoded protein is elevated in lung tumor tissue and in response to UV irradiation. Mutations in this gene cause autosomal-dominant polycystic kidney and liver disease. [provided by RefSeq, Jul 2016]

MANE transcript

NM_198334.3

Inheritance

ClinVar variants

P:61U:293B:164

Top phenotype

Polycystic kidney disease 3 with or without polycystic liver disease

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr11:62,624,826-62,646,726

External References & Databases

Ensembl (ENSG00000089597)

Transcript & Mutation Effects

hg38 • Region Span ~21.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant polycystic kidney diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: Orphanet

polycystic kidney disease 3 with or without polycystic liver diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010916

Submitter: Labcorp Genetics (formerly Invitae)

polycystic kidney disease 3 with or without polycystic liver diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010916

Submitter: Genomics England PanelApp

polycystic kidney disease 3 with or without polycystic liver diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010916

Submitter: PanelApp Australia

polycystic kidney disease 3 with or without polycystic liver diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010916

Submitter: ClinGen

GANAB was reported in relation to autosomal dominant polycystic kidney disease with or without polycystic liver disease in 2016 (Porath et al., PMID: 27259053). At least 11 unique variants (missense, frameshift, nonsense, indel) 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 11 probands in 3 publications (PMIDs: 27259053, 28375175, 29243290). This gene-disease association is supported by protein interaction studies and biochemical functional assays. In summary GANAB is definitively associated with autosomal dominant polycystic kidney disease with or without polycystic liver disease. This classification was approved by the ClinGen Cystic and Ciliopathy Disorders GCEP on 9/9/2020. (SOP Version 7).

Clinical Genomic Database (CGD)

Polycystic kidney disease 3 with or without polycystic liver diseaseAD

Manifestation: Cardiovascular; Gastrointestinal; Renal

Intervention: Cardiovascular; Gastrointestinal; Renal

Rationale: A number of manifestations can benefit from surveillance and early treatment, including surveillance for cardiovascular findings such as intracranial aneurysms and aortic dilation can allow early detection and treatment; Treatment for hypertension is frequently required (eg, with ACE inhibitors/angiotensin II receptor blockers); A number of agents should be avoided, including nephrotoxic agents, estrogens, smoking and agents that increase renal cysts; Additional considerations related to hepatic and other cyst-related manifestations may be beneficial

Refs: 27259053

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GANAB variants in ClinVar

13 Conditions Cataloged

not providedTotal: 405

Polycystic kidney disease 3 with or without polycystic liver diseaseTotal: 190

Inborn genetic diseasesTotal: 106

GANAB-related disorderTotal: 81

not specifiedTotal: 52

Autosomal dominant polycystic liver diseaseTotal: 15

POLYCYSTIC KIDNEY DISEASE 3 WITH POLYCYSTIC LIVER DISEASETotal: 5

Biliary tract abnormalityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198334.3. 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			10 clinvar	104 clinvar	3 clinvar	117
missense	3 clinvar	6 clinvar	274 clinvar	55 clinvar	2 clinvar	340
nonsense	4 clinvar	18 clinvar	2 clinvar			24
start loss						0
frameshift	7 clinvar	13 clinvar	1 clinvar			21
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar	6 clinvar			16
Total	17	44	293	159	5	518

Highest pathogenic variant AF is 0.0000061932883

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198334.3	RefSeq	NP_938148.1	24	MANE Select
ENST00000356638.8	Ensembl	ENSP00000349053.3	24	MANE Select
NM_001278192.2	RefSeq	NP_001265121.1	22	Standard
NM_001278193.2	RefSeq	NP_001265122.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
N-Glycan biosynthesis - Homo sapiens (human)
er associated degradation (erad) pathway
Calnexin/calreticulin cycle
Post-translational protein modification

Biological Process

carbohydrate metabolic process
N-glycan processing

Molecular Function

RNA binding
protein binding
carbohydrate binding
glucan 1,3-alpha-glucosidase activity

Cellular Component

endoplasmic reticulum lumen
Golgi apparatus
membrane
glucosidase II complex
melanosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000346178
Coding exons: 25
Length: 21807
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.24	429	581	0.738	0.0000342	6269
Missense (PolyPhen)		101	214.98	0.46981		2391
Synonymous	-1.32	238	213	1.11	0.0000113	1930
Loss of Function	6.22	10	63.5	0.158	0.00000402	605

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalytic subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins (PubMed:10929008). Required for PKD1/Polycystin-1 and PKD2/Polycystin-2 maturation and localization to the cell surface and cilia (PubMed:27259053). {ECO:0000269|PubMed:10929008, ECO:0000269|PubMed:27259053}.;
Disease: DISEASE: Note=GANAB variations may act as a disease modifier in autosomal dominant polycystic liver disease in patients who have causative mutations in other genes, such as PKHD1 or ALG8. {ECO:0000269|PubMed:28375157}.;

Recessive Scores

pRec: 0.229

Intolerance Scores

LoFtool: 0.0310
RVIS EVS: -0.66
RVIS percentile EVS: 16.02

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.558

Gene Damage Prediction

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