ATP6V0A2

ATPase H+ transporting V0 subunit a2, the group of V-type ATPase subunits

Basic information

Region (hg38): 12:123712352-123761755

Links

ENSG00000185344 ∙ NCBI:23545 ∙ OMIM:611716 ∙ HGNC:18481 ∙ Uniprot:Q9Y487 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive cutis laxa type 2, classic type (Strong), mode of inheritance: AR
• autosomal recessive cutis laxa type 2, classic type (Strong), mode of inheritance: AR
• wrinkly skin syndrome (Strong), mode of inheritance: AR
• wrinkly skin syndrome (Supportive), mode of inheritance: AR
• autosomal recessive cutis laxa type 2, classic type (Supportive), mode of inheritance: AR
• wrinkly skin syndrome (Definitive), mode of inheritance: AR
• autosomal recessive cutis laxa type 2A (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cutis laxa, autosomal recessive, type IIA; Wrinkly skin syndrome	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Biochemical; Craniofacial; Dental; Dermatologic; Musculoskeletal; Neurologic	15657616; 18157129; 17971833; 19401719; 22773132

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATP6V0A2 gene.

• ALG9 congenital disorder of glycosylation (317 variants)
• not provided (203 variants)
• Cutis laxa with osteodystrophy (161 variants)
• not specified (54 variants)
• Inborn genetic diseases (31 variants)
• Wrinkly skin syndrome;Cutis laxa with osteodystrophy (9 variants)
• Cutis laxa, recessive (9 variants)
• Wrinkly skin syndrome (8 variants)
• Cutis laxa with osteodystrophy;Wrinkly skin syndrome (7 variants)
• Cutis laxa (2 variants)
• Familial aplasia of the vermis (1 variants)
• Meckel-Gruber syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATP6V0A2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			8	82	5	95
missense		2	180	3	4	189
nonsense	7	1				8
start loss						0
frameshift	6	4				10
inframe indel			1	1		2
splice donor/acceptor (+/-2bp)	3	5	2	1		11
splice region			7	12	4	23
non coding			50	78	62	190
Total	16	12	241	165	71

Highest pathogenic variant AF is 0.0000131

Variants in ATP6V0A2

This is a list of pathogenic ClinVar variants found in the ATP6V0A2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-123712396-C-A		Cutis laxa, recessive • Cutis laxa with osteodystrophy	Uncertain significance (Jan 13, 2018)
12-123712418-C-T		Cutis laxa with osteodystrophy	Uncertain significance (Jan 13, 2018)
12-123712449-C-T		Cutis laxa with osteodystrophy	Likely benign (Jan 13, 2018)
12-123712452-G-A		Cutis laxa with osteodystrophy	Uncertain significance (Jan 12, 2018)
12-123712552-C-T		not specified • Familial aplasia of the vermis • Cutis laxa, recessive • Meckel-Gruber syndrome • Cutis laxa with osteodystrophy	Benign/Likely benign (Jan 13, 2018)
12-123712580-CCGGA-C		Cutis laxa with osteodystrophy	Likely pathogenic (Jan 25, 2023)
12-123712582-G-A		ALG9 congenital disorder of glycosylation	Uncertain significance (Sep 21, 2021)
12-123712583-G-A		ALG9 congenital disorder of glycosylation	Likely benign (Oct 06, 2020)
12-123712584-A-G		ALG9 congenital disorder of glycosylation	Uncertain significance (Jun 06, 2022)
12-123712591-C-T		Cutis laxa with osteodystrophy • Inborn genetic diseases • ALG9 congenital disorder of glycosylation	Uncertain significance (Dec 21, 2022)
12-123712593-A-G		ALG9 congenital disorder of glycosylation • Cutis laxa with osteodystrophy;Wrinkly skin syndrome • Inborn genetic diseases	Uncertain significance (Oct 24, 2022)
12-123712598-C-T		ALG9 congenital disorder of glycosylation	Likely benign (Dec 31, 2019)
12-123712599-C-G		ALG9 congenital disorder of glycosylation	Uncertain significance (May 25, 2021)
12-123712628-G-T		ALG9 congenital disorder of glycosylation	Likely benign (Jul 23, 2022)
12-123712630-C-T			Uncertain significance (Oct 01, 2019)
12-123712637-G-A		ALG9 congenital disorder of glycosylation	Likely benign (Aug 10, 2022)
12-123712642-T-TC		ALG9 congenital disorder of glycosylation • Cutis laxa	Pathogenic/Likely pathogenic (Jun 05, 2023)
12-123712643-C-G		ALG9 congenital disorder of glycosylation	Likely benign (Aug 19, 2022)
12-123712646-C-T		ALG9 congenital disorder of glycosylation	Likely benign (Jan 22, 2024)
12-123712654-G-A		Cutis laxa with osteodystrophy	Uncertain significance (Jan 13, 2018)
12-123712655-C-G		ALG9 congenital disorder of glycosylation	Likely benign (Jan 16, 2024)
12-123712667-G-T		ALG9 congenital disorder of glycosylation	Likely benign (Mar 13, 2023)
12-123712682-CG-C		ALG9 congenital disorder of glycosylation	Likely pathogenic (Feb 14, 2023)
12-123712689-G-A		ALG9 congenital disorder of glycosylation	Likely benign (Feb 14, 2023)
12-123712691-C-A		ALG9 congenital disorder of glycosylation	Likely benign (Aug 19, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATP6V0A2	protein_coding	protein_coding	ENST00000330342	20	49438

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.63e-11	0.999	125666	0	82	125748	0.000326

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.945	412	470	0.877	0.0000270	5628
Missense in Polyphen		151	202.52	0.74561		2512
Synonymous	-0.200	191	188	1.02	0.0000122	1613
Loss of Function	2.94	25	46.7	0.536	0.00000240	556

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000710	0.000687
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.000435	0.000381
Finnish	0.000970	0.000971
European (Non-Finnish)	0.000267	0.000264
Middle Eastern	0.000435	0.000381
South Asian	0.0000980	0.0000980
Other	0.000489	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Part of the proton channel of V-ATPases. Essential component of the endosomal pH-sensing machinery. May play a role in maintaining the Golgi functions, such as glycosylation maturation, by controlling the Golgi pH. In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633). {ECO:0000269|PubMed:16415858, ECO:0000269|PubMed:18157129, ECO:0000269|PubMed:28296633}.
• Disease: DISEASE: Cutis laxa, autosomal recessive, 2A (ARCL2A) [MIM:219200]: A disorder characterized by an excessive congenital skin wrinkling, a large fontanelle with delayed closure, a typical facial appearance with downslanting palpebral fissures, a general connective tissue weakness, and varying degrees of growth and developmental delay and neurological abnormalities. Some affected individuals develop seizures and mental deterioration later in life, whereas the skin phenotype tends to become milder with age. At the molecular level, an abnormal glycosylation of serum proteins is observed in many cases. {ECO:0000269|PubMed:18157129}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Wrinkly skin syndrome (WSS) [MIM:278250]: A rare autosomal recessive disorder characterized by wrinkling of the skin of the dorsum of the hands and feet, an increased number of palmar and plantar creases, wrinkled abdominal skin, multiple musculoskeletal abnormalities, microcephaly, growth failure and developmental delay. {ECO:0000269|PubMed:18157129}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Synaptic vesicle cycle - Homo sapiens (human);Phagosome - Homo sapiens (human);Lysosome - Homo sapiens (human);Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human);Oxidative phosphorylation - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Collecting duct acid secretion - Homo sapiens (human);Vibrio cholerae infection - Homo sapiens (human);Rheumatoid arthritis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Signal Transduction;Transferrin endocytosis and recycling;Ion channel transport;Insulin receptor recycling;Signaling by Insulin receptor;ROS, RNS production in phagocytes;Purine metabolism;Innate Immune System;Immune System;Transport of small molecules;Iron uptake and transport;Signaling by Receptor Tyrosine Kinases (Consensus)

Recessive Scores

• pRec: 0.374

Intolerance Scores

• loftool: 0.161
• rvis_EVS: -0.62
• rvis_percentile_EVS: 17.47

Haploinsufficiency Scores

• pHI: 0.256
• hipred: Y
• hipred_score: 0.542
• ghis: 0.597

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.163

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Atp6v0a2

Gene ontology

• Biological process: cellular iron ion homeostasis;immune response;vacuolar acidification;insulin receptor signaling pathway;ATP hydrolysis coupled proton transport;regulation of macroautophagy;transferrin transport;ion transmembrane transport;cellular response to increased oxygen levels
• Cellular component: vacuolar proton-transporting V-type ATPase, V0 domain;acrosomal vesicle;lysosomal membrane;plasma membrane;endosome membrane;integral component of membrane;vacuolar proton-transporting V-type ATPase complex;phagocytic vesicle membrane
• Molecular function: protein binding;proton-transporting ATPase activity, rotational mechanism;ATPase binding