ATP6V1B2

protein-coding

ATPase H+ transporting V1 subunit B2, the group of ATPase F1/V1 alpha/A and beta/B subunit family|V-type ATPase subunits

Gene summary

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts. [provided by RefSeq, Jul 2008]

Previous symbols:

VPP3
ATP6B2

MANE transcript

NM_001693.4

Inheritance

AD, AR

ClinVar variants

P:18U:126B:33

Top phenotype

Deafness, congenital, with onychodystrophy, autosomal dominant; Zimmermann-Laband syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr8:20,197,381-20,230,399

External References & Databases

Ensembl (ENSG00000147416)

Transcript & Mutation Effects

hg38 • Region Span ~33.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

DOORS syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009079

Submitter: PanelApp Australia

Zimmermann-Laband syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014646

Submitter: G2P

autosomal dominant deafness - onychodystrophy syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007420

Submitter: Labcorp Genetics (formerly Invitae)

Zimmermann-Laband syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000200

Submitter: Orphanet

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

developmental and epileptic encephalopathy 93STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020632

Submitter: Labcorp Genetics (formerly Invitae)

DOORS syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009079

Submitter: Orphanet

autosomal dominant deafness - onychodystrophy syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007420

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, congenital, with onychodystrophy, autosomal dominant; Zimmermann-Laband syndrome 2AD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Dermatologic; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 18541964; 23994350; 24913193; 25915598

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP6V1B2 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 83

Inborn genetic diseasesTotal: 68

not specifiedTotal: 39

Zimmermann-Laband syndrome 2Total: 23

Autosomal dominant deafness - onychodystrophy syndromeTotal: 14

ATP6V1B2-related disorderTotal: 7

Cataract 10 multiple typesTotal: 1

Zimmermann-Laband syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001693.4. 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			2 clinvar	20 clinvar		22
missense	4 clinvar	10 clinvar	111 clinvar	12 clinvar	1 clinvar	138
nonsense	3 clinvar	1 clinvar	5 clinvar			9
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	7	11	126	32	1	177

Highest pathogenic variant AF is 0.0000023188406

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001693.4	RefSeq	NP_001684.2	14	MANE Select
ENST00000276390.7	Ensembl	ENSP00000276390.2	14	MANE Select
ENST00000519667.1	Ensembl	ENSP00000430682.1	6	Standard
ENST00000520830.1	Ensembl	ENSP00000428069.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mTOR signaling pathway - Homo sapiens (human)
Synaptic vesicle cycle - Homo sapiens (human)
Phagosome - Homo sapiens (human)
Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)

Biological Process

insulin receptor signaling pathway
ATP hydrolysis coupled proton transport
regulation of macroautophagy
transferrin transport
ion transmembrane transport

Molecular Function

protein binding
ATP binding
proton transmembrane transporter activity
proton-transporting ATPase activity, rotational mechanism

Cellular Component

ruffle
lysosomal membrane
cytosol
plasma membrane
microvillus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000276390
Coding exons: 14
Length: 29453
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125731
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.49	172	291	0.590	0.0000157	3310
Missense (PolyPhen)		27	113.33	0.23824		1236
Synonymous	-1.05	121	107	1.13	0.00000613	1015
Loss of Function	4.58	4	31.9	0.125	0.00000209	323

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-catalytic subunit of the peripheral V1 complex of vacuolar ATPase. V-ATPase is responsible for acidifying a variety of intracellular compartments in eukaryotic cells.;
Disease: DISEASE: Zimmermann-Laband syndrome 2 (ZLS2) [MIM:616455]: A disorder characterized by gingival fibromatosis, dysplastic or absent nails, finger abnormalities, hepatosplenomegaly, and abnormalities of the cartilage of the nose and/or ears. {ECO:0000269|PubMed:25915598}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, congenital, with onychodystrophy, autosomal dominant (DDOD) [MIM:124480]: An autosomal dominant syndrome characterized mainly by congenital sensorineural hearing loss accompanied by dystrophic or absent nails. Coniform teeth, selective tooth agenesis, and hands and feet abnormalities are present in some patients. {ECO:0000269|PubMed:24913193}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.279

Intolerance Scores

LoFtool: 0.146
RVIS EVS: -0.45
RVIS percentile EVS: 24.33

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.655

Gene Damage Prediction

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