Diabetes mellitus, permanent neonatal 3: genes and variants

Genes linked to Diabetes mellitus, permanent neonatal 3

• ABCC8: ATP-binding cassette sub-family C member 8

  It senses cellular nucleotide levels as the regulatory component of pancreatic beta-cell ATP-sensitive potassium channels and thereby couples glucose metabolism to insulin secretion. Loss-of-function variants cause congenital hyperinsulinism, whereas activating variants can cause neonatal diabetes.

  17 disease-causing and 27 uncertain variants in ABCC8 are linked to Diabetes mellitus, permanent neonatal 3.

• INS: Insulin

  After processing to insulin, it lowers blood glucose by promoting cellular glucose uptake, glycogen and lipid synthesis, and suppression of hepatic glucose production. Pathogenic variants can cause neonatal diabetes, maturity-onset diabetes of the young, or hyperproinsulinemia depending on their effect on folding and secretion.

  11 disease-causing and 16 uncertain variants in INS are linked to Diabetes mellitus, permanent neonatal 3.

• KCNJ11: ATP-sensitive inward rectifier potassium channel 11

  Together with SUR1, its ATP-sensitive potassium conductance couples pancreatic beta-cell metabolism to membrane depolarization and insulin secretion. Activating variants cause neonatal diabetes, whereas loss-of-function variants can cause congenital hyperinsulinism.

  7 disease-causing and 11 uncertain variants in KCNJ11 are linked to Diabetes mellitus, permanent neonatal 3.

Where Diabetes mellitus, permanent neonatal 3 variants cluster

• ABCC8 ABC transporter 2 (positions 1344–1578): 8 of 17 disease-causing changes, 3.2× more than its size predicts.
• KCNJ11 Cytoplasmic (positions 172–390): 6 of 7 disease-causing changes, 1.5× more than its size predicts.

Known disease-causing variants in Diabetes mellitus, permanent neonatal 3

Uncertain variants in Diabetes mellitus, permanent neonatal 3 that look disease-causing

Which prediction tools work for Diabetes mellitus, permanent neonatal 3

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 97 out of 100
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• CATVariant: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 80 out of 100
• MetaLR: 76 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 74 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 58 out of 100

Same protein, different disease

• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by ABCC8 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (31 disease-causing).
• Type 2 diabetes mellitus is also caused by ABCC8 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (27 disease-causing).
• Hereditary hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (22 disease-causing).
• Familial hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (20 disease-causing).
• Diabetes mellitus, transient neonatal, 2 is also caused by ABCC8 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (19 disease-causing).
• Neonatal diabetes mellitus is also caused by INS variants; they fall partly in the same places as the Diabetes mellitus, permanent neonatal 3 variants (11 disease-causing).
• Hyperproinsulinemia is also caused by INS variants; they fall in the same places as the Diabetes mellitus, permanent neonatal 3 variants (6 disease-causing).
• Maturity-onset diabetes of the young is also caused by INS variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (3 disease-causing).
• Neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (8 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by KCNJ11 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (7 disease-causing).
• Diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (6 disease-causing).
• Familial hyperinsulinism is also caused by KCNJ11 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (6 disease-causing).
• Permanent neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Diabetes mellitus, permanent neonatal 3 variants (6 disease-causing).

Diseases related to Diabetes mellitus, permanent neonatal 3

• Monogenic diabetes, also linked to ABCC8, INS and KCNJ11
• Maturity-onset diabetes of the young, also linked to ABCC8, INS and KCNJ11
• Type 2 diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Neonatal diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Permanent neonatal diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Hyperinsulinemic hypoglycemia, familial, 1, also linked to ABCC8 and KCNJ11
• Familial hyperinsulinism, also linked to ABCC8 and KCNJ11
• Diabetes mellitus, transient neonatal, 2, also linked to ABCC8 and KCNJ11
• Atrial septal defect, also linked to ABCC8
• Pulmonary arterial hypertension, also linked to ABCC8
• Hereditary hyperinsulinism, also linked to ABCC8

Frequently asked questions

Which genes are linked to Diabetes mellitus, permanent neonatal 3?

In CATVariant, Diabetes mellitus, permanent neonatal 3 is linked to 3 analyzed proteins: ABCC8 (ATP-binding cassette sub-family C member 8), INS (Insulin) and KCNJ11 (ATP-sensitive inward rectifier potassium channel 11).

How many genetic variants are linked to Diabetes mellitus, permanent neonatal 3?

116 variants: 35 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 54 are of uncertain significance or have conflicting reports.

Which uncertain variants in Diabetes mellitus, permanent neonatal 3 look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example ABCC8 R1352H. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Diabetes mellitus, permanent neonatal 3?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 19 disease-causing and 9 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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