ABCC8

ATP binding cassette subfamily C member 8, the group of ATP binding cassette subfamily C

Basic information

Region (hg38): 11:17392498-17476894

Previous symbols: [ "SUR", "HRINS" ]

Links

ENSG00000006071 ∙ NCBI:6833 ∙ OMIM:600509 ∙ HGNC:59 ∙ Uniprot:Q09428 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hyperinsulinemic hypoglycemia, familial, 1 (Definitive), mode of inheritance: AD
• familial hyperinsulinism (Definitive), mode of inheritance: AR
• hyperinsulinemic hypoglycemia, familial, 1 (Strong), mode of inheritance: AD
• diabetes mellitus, permanent neonatal 3 (Strong), mode of inheritance: AD
• hyperinsulinemic hypoglycemia, familial, 1 (Strong), mode of inheritance: AR
• diabetes mellitus, permanent neonatal 3 (Strong), mode of inheritance: AR
• transient neonatal diabetes mellitus (Strong), mode of inheritance: AD
• diabetes mellitus, noninsulin-dependent (Strong), mode of inheritance: AD
• diabetes mellitus, transient neonatal, 2 (Strong), mode of inheritance: Unknown
• hypoglycemia, leucine-induced (Strong), mode of inheritance: AD
• permanent neonatal diabetes mellitus (Strong), mode of inheritance: AR
• diabetes mellitus, permanent neonatal 3 (Definitive), mode of inheritance: Semidominant
• hyperinsulinemic hypoglycemia, familial, 1 (Definitive), mode of inheritance: Semidominant
• maturity-onset diabetes of the young (Supportive), mode of inheritance: AD
• DEND syndrome (Supportive), mode of inheritance: AD
• autosomal recessive hyperinsulinism due to SUR1 deficiency (Supportive), mode of inheritance: AR
• permanent neonatal diabetes mellitus (Supportive), mode of inheritance: AD
• transient neonatal diabetes mellitus (Supportive), mode of inheritance: AD
• autosomal dominant hyperinsulinism due to SUR1 deficiency (Supportive), mode of inheritance: AD
• diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency (Supportive), mode of inheritance: AD
• diabetes mellitus, transient neonatal, 2 (Strong), mode of inheritance: AD
• diabetes mellitus, permanent neonatal 3 (Strong), mode of inheritance: AR
• type 2 diabetes mellitus (Limited), mode of inheritance: AD
• hyperinsulinemic hypoglycemia, familial, 1 (Strong), mode of inheritance: AD
• hyperinsulinemic hypoglycemia, familial, 1 (Strong), mode of inheritance: AR
• pulmonary arterial hypertension (Moderate), mode of inheritance: AD
• monogenic diabetes (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Diabetes mellitus, transient neonatal, 2; Diabetes, permanent neonatal 3; Hyperinsulinemic hypoglycemia, familial, 1; Hypoglycemia, leucine-induced	AD/AR	Endocrine	Prompt treatment (eg, of ketoacidosis and dehydration) can avoid morbidity; Individuals with neonatal diabetes mellitus may respond well to sulfonylurea treatment; Non-neonatally affected individuals may respond to diazoxide; Individuals with leucine-induced hypoglycemia may have episodes triggered by high-protein (high leucine) feedings, and may respond to diazoxide	Endocrine	7847376; 7716548; 923011; 8751851; 9727845; 10426386; 10322395; 11808881; 10334322; 1018078; 12559865; 12941782; 15356046; 15579781; 16885549; 16882742; 16613899; 8596924; 19254908; 20301620; 21716120; 23273570
Hyperinsulinemic hypoglycemia, familial, 1 inheritance may involve imprinting

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ABCC8 gene.

• not provided (112 variants)
• Hyperinsulinemic hypoglycemia, familial, 1 (34 variants)
• Type 2 diabetes mellitus (34 variants)
• Familial hyperinsulinism (12 variants)
• Hereditary hyperinsulinism (10 variants)
• ABCC8-related disorder (4 variants)
• Diabetes mellitus, permanent neonatal 3;Type 2 diabetes mellitus;Hyperinsulinemic hypoglycemia, familial, 1;Leucine-induced hypoglycemia;Diabetes mellitus, transient neonatal, 2 (2 variants)
• Inborn genetic diseases (2 variants)
• Diabetes mellitus, transient neonatal, 2;Hyperinsulinemic hypoglycemia, familial, 1;Leucine-induced hypoglycemia;Diabetes mellitus, permanent neonatal 3;Type 2 diabetes mellitus (1 variants)
• Hyperinsulinemic hypoglycemia, familial, 1;Leucine-induced hypoglycemia;Diabetes mellitus, transient neonatal, 2;Type 2 diabetes mellitus;Diabetes mellitus, permanent neonatal 3 (1 variants)
• Monogenic diabetes (1 variants)
• Permanent neonatal diabetes mellitus (1 variants)
• See cases (1 variants)
• Diabetes mellitus, transient neonatal, 2;Diabetes mellitus, permanent neonatal 3;Hyperinsulinemic hypoglycemia, familial, 1;Leucine-induced hypoglycemia;Type 2 diabetes mellitus (1 variants)
• Leucine-induced hypoglycemia;Hyperinsulinemic hypoglycemia, familial, 1;Permanent neonatal diabetes mellitus;Diabetes mellitus, transient neonatal, 2;Type 2 diabetes mellitus (1 variants)
• Diabetes mellitus, permanent neonatal 3;Hyperinsulinemic hypoglycemia, familial, 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ABCC8 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			13	640	2	655
missense	24	87	324	11	1	447
nonsense	49	35				84
start loss	4	1				5
frameshift	44	58	3			105
inframe indel		2	16			18
splice donor/acceptor (+/-2bp)	17	48	2			67
splice region			18	121	2	141
non coding	1	4	17	351	74	447
Total	139	235	375	1002	77

Highest pathogenic variant AF is 0.000177

Variants in ABCC8

This is a list of pathogenic ClinVar variants found in the ABCC8 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-17392873-T-C		Hyperinsulinism, Dominant/Recessive • Permanent neonatal diabetes mellitus • Transient Neonatal Diabetes, Dominant • Transitory neonatal diabetes mellitus • Maturity onset diabetes mellitus in young	Conflicting classifications of pathogenicity (Jun 14, 2016)
11-17392898-A-T		Diabetes mellitus, transient neonatal, 2 • Hyperinsulinemic hypoglycemia, familial, 1 • Permanent neonatal diabetes mellitus • Maturity onset diabetes mellitus in young • Transitory neonatal diabetes mellitus	Uncertain significance (Jan 13, 2018)
11-17392984-T-G		not specified	Uncertain significance (Nov 10, 2020)
11-17393004-C-G			Uncertain significance (Dec 23, 2022)
11-17393004-C-T		Hereditary hyperinsulinism • not specified • Transitory neonatal diabetes mellitus • Maturity onset diabetes mellitus in young	Conflicting classifications of pathogenicity (Apr 12, 2021)
11-17393008-C-T			Uncertain significance (Aug 22, 2022)
11-17393009-G-A		not specified • Maturity onset diabetes mellitus in young • Permanent neonatal diabetes mellitus • Transient Neonatal Diabetes, Dominant • Hyperinsulinism, Dominant/Recessive • Hyperinsulinemic hypoglycemia, familial, 1 • Diabetes mellitus, transient neonatal, 2 • Hereditary hyperinsulinism • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 31, 2024)
11-17393015-G-A			Likely benign (Sep 05, 2023)
11-17393015-G-C			Likely benign (Oct 31, 2022)
11-17393017-C-T			Uncertain significance (Sep 01, 2021)
11-17393018-G-A			Likely benign (Nov 17, 2023)
11-17393023-C-T		not specified • Permanent neonatal diabetes mellitus • Transient Neonatal Diabetes, Dominant • Maturity onset diabetes mellitus in young • Hyperinsulinism, Dominant/Recessive • Diabetes mellitus, transient neonatal, 2 • Hyperinsulinemic hypoglycemia, familial, 1 • Leucine-induced hypoglycemia • Neonatal hypoglycemia • Diabetes mellitus, permanent neonatal 3 • Hereditary hyperinsulinism	Conflicting classifications of pathogenicity (Feb 01, 2024)
11-17393024-G-A		Hereditary hyperinsulinism • Transitory neonatal diabetes mellitus • Maturity onset diabetes mellitus in young	Conflicting classifications of pathogenicity (Jun 06, 2023)
11-17393027-G-A			Likely benign (May 22, 2023)
11-17393030-C-T			Likely benign (Nov 24, 2023)
11-17393033-C-G			Likely benign (Sep 12, 2023)
11-17393033-C-T			Likely benign (Aug 02, 2023)
11-17393034-C-T		Hereditary hyperinsulinism • Transitory neonatal diabetes mellitus • Maturity onset diabetes mellitus in young • Leucine-induced hypoglycemia	Conflicting classifications of pathogenicity (Jun 21, 2024)
11-17393035-G-T			Likely benign (Oct 18, 2023)
11-17393039-G-A			Likely benign (May 07, 2023)
11-17393045-C-A		ABCC8-related disorder	Uncertain significance (Jun 14, 2024)
11-17393047-T-C		Hyperinsulinemic hypoglycemia, familial, 1 • Diabetes mellitus, transient neonatal, 2 • Permanent neonatal diabetes mellitus	Conflicting classifications of pathogenicity (Jan 27, 2024)
11-17393051-T-C			Likely benign (May 04, 2022)
11-17393051-TG-T		Hyperinsulinemic hypoglycemia, familial, 1 • Transitory neonatal diabetes mellitus • Maturity onset diabetes mellitus in young	Conflicting classifications of pathogenicity (Mar 24, 2017)
11-17393054-C-T			Likely benign (Mar 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ABCC8	protein_coding	protein_coding	ENST00000389817	39	84018

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.96e-24	0.999	125632	0	116	125748	0.000461

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.91	752	915	0.822	0.0000593	10229
Missense in Polyphen		159	231.98	0.68541		2681
Synonymous	-0.853	409	388	1.06	0.0000268	3228
Loss of Function	3.35	51	84.2	0.606	0.00000456	892

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000785	0.000771
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000386	0.000326
Finnish	0.000238	0.000231
European (Non-Finnish)	0.000557	0.000554
Middle Eastern	0.000386	0.000326
South Asian	0.000591	0.000588
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Subunit of the beta-cell ATP-sensitive potassium channel (KATP). Regulator of ATP-sensitive K(+) channels and insulin release. {ECO:0000269|PubMed:24814349, ECO:0000269|PubMed:25720052}.
• Disease: DISEASE: Leucine-induced hypoglycemia (LIH) [MIM:240800]: Rare cause of hypoglycemia and is described as a condition in which symptomatic hypoglycemia is provoked by high protein feedings. Hypoglycemia is also elicited by administration of oral or intravenous infusions of a single amino acid, leucine. {ECO:0000269|PubMed:15356046}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial hyperinsulinemic hypoglycemia 1 (HHF1) [MIM:256450]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269|PubMed:10202168, ECO:0000269|PubMed:10334322, ECO:0000269|PubMed:10615958, ECO:0000269|PubMed:11018078, ECO:0000269|PubMed:11226335, ECO:0000269|PubMed:11867634, ECO:0000269|PubMed:12364426, ECO:0000269|PubMed:12941782, ECO:0000269|PubMed:15562009, ECO:0000269|PubMed:15579781, ECO:0000269|PubMed:15807877, ECO:0000269|PubMed:16357843, ECO:0000269|PubMed:16429405, ECO:0000269|PubMed:24814349, ECO:0000269|PubMed:25720052, ECO:0000269|PubMed:8650576, ECO:0000269|PubMed:8751851, ECO:0000269|PubMed:8923011, ECO:0000269|PubMed:9618169, ECO:0000269|PubMed:9648840, ECO:0000269|PubMed:9769320}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, permanent neonatal (PNDM) [MIM:606176]: A rare form of diabetes distinct from childhood- onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy. {ECO:0000269|PubMed:16613899, ECO:0000269|PubMed:16885549, ECO:0000269|PubMed:17213273, ECO:0000269|PubMed:17668386}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Transient neonatal diabetes mellitus 2 (TNDM2) [MIM:610374]: Neonatal diabetes is a form of diabetes mellitus defined by the onset of mild-to-severe hyperglycemia within the first months of life. Transient neonatal diabetes remits early, with a possible relapse during adolescence. {ECO:0000269|PubMed:16885549}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Type II diabetes mellitus - Homo sapiens (human);ABC transporters - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics;Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Glibenclamide Action Pathway;Gliclazide Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Pancreas Function;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Repaglinide Action Pathway;Nateglinide Action Pathway;Defective ABCC8 can cause hypoglycemias and hyperglycemias;Disorders of transmembrane transporters;Disease;Metabolism;Regulation of insulin secretion;Neuronal System;ATP sensitive Potassium channels;Integration of energy metabolism;ABC transporter disorders;Inwardly rectifying K+ channels;Potassium Channels;FOXA2 and FOXA3 transcription factor networks (Consensus)

Recessive Scores

• pRec: 0.435

Intolerance Scores

• loftool: 0.0423
• rvis_EVS: -2.09
• rvis_percentile_EVS: 1.57

Haploinsufficiency Scores

• pHI: 0.150
• hipred: Y
• hipred_score: 0.771
• ghis: 0.635

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.718

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Abcc8
• Phenotype: endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: cellular glucose homeostasis;potassium ion transport;female pregnancy;memory;visual learning;response to pH;response to zinc ion;negative regulation of low-density lipoprotein particle clearance;negative regulation of angiogenesis;response to lipopolysaccharide;positive regulation of tumor necrosis factor production;response to insulin;response to drug;negative regulation of insulin secretion;regulation of insulin secretion;transmembrane transport;negative regulation of glial cell proliferation;negative regulation of wound healing;negative regulation of neuroblast migration;cellular response to organic substance;potassium ion transmembrane transport;positive regulation of uterine smooth muscle relaxation;positive regulation of voltage-gated potassium channel activity;positive regulation of tight junction disassembly;negative regulation of maintenance of permeability of blood-brain barrier
• Cellular component: mitochondrion;plasma membrane;inward rectifying potassium channel;membrane;synaptic vesicle membrane;sarcolemma
• Molecular function: potassium channel activity;ATP binding;sulfonylurea receptor activity;ATP-activated inward rectifier potassium channel activity;ATPase activity, coupled to transmembrane movement of substances;ion channel binding