ABCC6

ATP binding cassette subfamily C member 6, the group of ATP binding cassette subfamily C

Basic information

Region (hg38): 16:16149565-16223522

Previous symbols: [ "ARA", "PXE" ]

Links

ENSG00000091262 ∙ NCBI:368 ∙ OMIM:603234 ∙ HGNC:57 ∙ Uniprot:O95255 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• arterial calcification, generalized, of infancy, 2 (Definitive), mode of inheritance: AR
• autosomal recessive inherited pseudoxanthoma elasticum (Definitive), mode of inheritance: AR
• autosomal recessive inherited pseudoxanthoma elasticum (Supportive), mode of inheritance: AR
• arterial calcification of infancy (Supportive), mode of inheritance: AD
• autosomal recessive inherited pseudoxanthoma elasticum (Strong), mode of inheritance: AR
• autosomal recessive inherited pseudoxanthoma elasticum (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pseudoxanthoma elasticum (including Pseudoxanthoma elasticum, forme fruste)	AD/AR/Digenic	Cardiovascular; Hematologic; Ophthalmologic	Preventive measures (eg, weight control, avoidance of smoking, and medical management of hypertension and hypercholesterolemia) related to cardiovascular risk factors may be beneficial by decreasing contributory factors related to atherosclerosis; Awareness may allow surveillance for and early detection and treatment of cardiovascular (eg, surgical interventions related to vascular disease) and hematologic manifestations (eg, interventions related to GI bleeding); Standard treatment for macular degeneration (including intraocular injection of anti-angiogenic drugs) may be beneficial, and awareness of ophthalmologic aspects may allow early detection and treatment; Circumstances such as contact sports and the use of medications that increase the risk of GI bleeding should be avoided	Cardiovascular; Dermatologic; Hematologic; Ophthalmologic	14068068; 3652487; 3342167; 2012127; 1600795; 8413390; 10619263; 10835643; 10835642; 10811882; 11209132; 15098239; 16086317; 18157818; 18800149; 19298904; 20034067; 20075945; 20301292; 21210805; 21386758; 21671388; 22209248; 23675997; 23746223; 23935882; 23968982; 23978319; 24008425; 24749718
In recessive forms, heterozygotes may have mild manifestations; Digenic inheritance (with GGCX) has been reported

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ABCC6 gene.

• not_provided (1226 variants)
• Autosomal_recessive_inherited_pseudoxanthoma_elasticum (707 variants)
• Arterial_calcification,_generalized,_of_infancy,_2 (455 variants)
• Pseudoxanthoma_elasticum,_forme_fruste (452 variants)
• Inborn_genetic_diseases (146 variants)
• ABCC6-related_disorder (90 variants)
• not_specified (37 variants)
• Retinal_dystrophy (13 variants)
• See_cases (6 variants)
• Optic_atrophy (2 variants)
• Abnormality_of_the_eye (2 variants)
• Papule (1 variants)
• Finnish_congenital_nephrotic_syndrome (1 variants)
• Cutis_laxa (1 variants)
• Pseudoxanthoma_elasticum (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ABCC6 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000001171.6. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1		23	335	10	369
missense	39	91	632	44	8	814
nonsense	29	32	2			63
start loss						0
frameshift	38	52	3			93
splice donor/acceptor (+/-2bp)	11	27	4			42
Total	118	202	664	379	18

Highest pathogenic variant AF is 0.00161284

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ABCC6	protein_coding	protein_coding	ENST00000205557	31	74595

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.62e-35	0.00158	125040	0	708	125748	0.00282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.09	926	837	1.11	0.0000531	9576
Missense in Polyphen		222	216.8	1.024		2380
Synonymous	-1.09	391	365	1.07	0.0000239	3223
Loss of Function	1.36	60	72.5	0.828	0.00000361	781

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00236	0.00235
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.00440	0.00436
Finnish	0.00431	0.00431
European (Non-Finnish)	0.00378	0.00376
Middle Eastern	0.00440	0.00436
South Asian	0.000916	0.000915
Other	0.00278	0.00277

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Isoform 1: May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Transports glutathione conjugates as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS). {ECO:0000269|PubMed:11880368}.
• Disease: DISEASE: Pseudoxanthoma elasticum (PXE) [MIM:264800]: A multisystem disorder characterized by accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Burch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye including peau d'orange, angioid streaks, and choroidal neovascularizations, of the skin including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces, and of the cardiovascular system with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings. {ECO:0000269|PubMed:10811882, ECO:0000269|PubMed:10835642, ECO:0000269|PubMed:10954200, ECO:0000269|PubMed:11427982, ECO:0000269|PubMed:11536079, ECO:0000269|PubMed:11702217, ECO:0000269|PubMed:11880368, ECO:0000269|PubMed:15086542, ECO:0000269|PubMed:15098239, ECO:0000269|PubMed:15459974, ECO:0000269|PubMed:16086317, ECO:0000269|PubMed:17617515, ECO:0000269|PubMed:19339160, ECO:0000269|PubMed:20034067, ECO:0000269|PubMed:25615550}. Note=The disease is caused by mutations affecting the gene represented in this entry. Homozygous or compound heterozygous ABCC6 mutations have been found in the overwhelming majority of cases. Individuals carrying heterozygous mutations express limited manifestations of the pseudoxanthoma elasticum phenotype.; DISEASE: Arterial calcification of infancy, generalized, 2 (GACI2) [MIM:614473]: A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure. {ECO:0000269|PubMed:22209248}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: ABC transporters - Homo sapiens (human);Photodynamic therapy-induced NFE2L2 (NRF2) survival signaling;Transport of small molecules;ABC-family proteins mediated transport (Consensus)

Intolerance Scores

• loftool: 0.0194
• rvis_EVS: 0.63
• rvis_percentile_EVS: 83.54

Haploinsufficiency Scores

• pHI: 0.125
• hipred: N
• hipred_score: 0.492
• ghis: 0.435

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.159

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Abcc6
• Phenotype: craniofacial phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; vision/eye phenotype; renal/urinary system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: abcc6b.2
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: dead

Gene ontology

• Biological process: visual perception;response to drug;transmembrane transport;ATP hydrolysis coupled anion transmembrane transport
• Cellular component: nucleus;vacuolar membrane;endoplasmic reticulum membrane;plasma membrane;membrane;integral component of membrane;basolateral plasma membrane;apical plasma membrane;lateral plasma membrane
• Molecular function: transporter activity;ATP binding;ATPase activity, coupled to transmembrane movement of substances;ATPase-coupled anion transmembrane transporter activity