Seizures, benign familial infantile, 3: genes and variants

Genes linked to Seizures, benign familial infantile, 3

• SCN2A: Sodium channel protein type 2 subunit alpha

  The protein forms Nav1.2, a voltage-gated sodium channel that carries sodium current during neuronal action potentials. By shaping neuronal excitability and signal propagation, it supports brain circuits involved in development, learning, and seizure susceptibility.

  167 disease-causing and 688 uncertain variants in SCN2A are linked to Seizures, benign familial infantile, 3.

• SCN8A: Sodium channel protein type 8 subunit alpha

  The protein forms Nav1.6, a voltage-gated sodium channel that sets the threshold and propagation of neuronal action potentials. It is widely important for neuronal excitability, and SCN8A variants are associated with developmental and epileptic encephalopathies.

  12 disease-causing and 25 uncertain variants in SCN8A are linked to Seizures, benign familial infantile, 3.

• PRRT2: Proline-rich transmembrane protein 2

  It modulates presynaptic neurotransmitter release and neuronal excitability through interactions with SNARE machinery and ion channels. Haploinsufficiency commonly causes paroxysmal kinesigenic dyskinesia, self-limited infantile seizures, or the combined infantile-convulsions-and-choreoathetosis phenotype.

  3 disease-causing and 10 uncertain variants in PRRT2 are linked to Seizures, benign familial infantile, 3.

• KCNQ3: Potassium voltage-gated channel subfamily KQT member 3

  Together with KCNQ2, its slowly activating current provides much of the neuronal M-current that suppresses repetitive firing. Pathogenic variants can cause self-limited neonatal epilepsy or more severe developmental and epileptic encephalopathy.

  1 disease-causing and 0 uncertain variants in KCNQ3 are linked to Seizures, benign familial infantile, 3.

Where Seizures, benign familial infantile, 3 variants cluster

• SCN2A S4 of repeat IV (positions 1624–1640): 16 of 167 disease-causing changes, 11.3× more than its size predicts.
• SCN8A S4 of repeat I (positions 218–234): 3 of 12 disease-causing changes, 29.1× more than its size predicts.
• SCN2A Extracellular (positions 209–214): 5 of 167 disease-causing changes, 10.0× more than its size predicts.
• SCN2A Cytoplasmic (positions 1470–1532): 15 of 167 disease-causing changes, 2.9× more than its size predicts.
• SCN2A S4 of repeat I (positions 215–231): 6 of 167 disease-causing changes, 4.2× more than its size predicts.

Known disease-causing variants in Seizures, benign familial infantile, 3

Showing 60 of 183.

Uncertain variants in Seizures, benign familial infantile, 3 that look disease-causing

Which prediction tools work for Seizures, benign familial infantile, 3

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

• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 94 out of 100
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• ESM1b (LLR): 91 out of 100
• CADD: 90 out of 100
• MutPred2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 87 out of 100
• PolyPhen-2: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 79 out of 100
• phyloP: 63 out of 100

Same protein, different disease

• Complex neurodevelopmental disorder is also caused by SCN2A variants; they fall partly in the same places as the Seizures, benign familial infantile, 3 variants (22 disease-causing).
• Episodic ataxia type 2 is also caused by SCN2A variants; they fall in the same places as the Seizures, benign familial infantile, 3 variants (15 disease-causing).
• West syndrome is also caused by SCN2A variants; they fall partly in the same places as the Seizures, benign familial infantile, 3 variants (11 disease-causing).
• Benign familial infantile epilepsy is also caused by SCN2A variants; they fall partly in the same places as the Seizures, benign familial infantile, 3 variants (6 disease-causing).
• Infantile spasms is also caused by SCN2A variants; they fall in the same places as the Seizures, benign familial infantile, 3 variants (3 disease-causing).
• Early-infantile DEE is also caused by SCN8A variants; they fall mostly in different places as the Seizures, benign familial infantile, 3 variants (90 disease-causing).
• Cognitive impairment with or without cerebellar ataxia is also caused by SCN8A variants; they fall mostly in different places as the Seizures, benign familial infantile, 3 variants (22 disease-causing).
• Complex neurodevelopmental disorder is also caused by SCN8A variants; they fall mostly in different places as the Seizures, benign familial infantile, 3 variants (8 disease-causing).
• Autosomal recessive inheritance is also caused by SCN8A variants; they fall mostly in different places as the Seizures, benign familial infantile, 3 variants (3 disease-causing).
• Myoclonus, familial, 2 is also caused by SCN8A variants; they fall mostly in different places as the Seizures, benign familial infantile, 3 variants (3 disease-causing).
• Episodic kinesigenic dyskinesia is also caused by PRRT2 variants; they fall partly in the same places as the Seizures, benign familial infantile, 3 variants (8 disease-causing).
• Benign neonatal seizures is also caused by KCNQ3 variants; they fall mostly in different places as the Seizures, benign familial infantile, 3 variants (13 disease-causing).
• Seizures, benign familial neonatal, 1 is also caused by KCNQ3 variants; they fall mostly in different places as the Seizures, benign familial infantile, 3 variants (7 disease-causing).

Diseases related to Seizures, benign familial infantile, 3

• Epilepsy, also linked to KCNQ3, SCN2A and SCN8A
• Amyotrophic lateral sclerosis, also linked to SCN2A and SCN8A
• Cardiac arrhythmia, also linked to SCN2A and SCN8A
• Complex neurodevelopmental disorder, also linked to SCN2A and SCN8A
• Self-limited epilepsy with centrotemporal spikes, also linked to KCNQ3 and SCN2A
• Benign familial infantile epilepsy, also linked to PRRT2 and SCN2A
• Infantile spasms, also linked to SCN2A and SCN8A
• Genetic developmental and epileptic encephalopathy, also linked to SCN2A and SCN8A
• Lennox-Gastaut syndrome, also linked to SCN2A and SCN8A
• Early-infantile DEE, also linked to SCN8A
• Episodic ataxia type 2, also linked to SCN2A
• Seizures, benign familial neonatal, 1, also linked to KCNQ3

Frequently asked questions

Which genes are linked to Seizures, benign familial infantile, 3?

In CATVariant, Seizures, benign familial infantile, 3 is linked to 4 analyzed proteins: SCN2A (Sodium channel protein type 2 subunit alpha), SCN8A (Sodium channel protein type 8 subunit alpha), PRRT2 (Proline-rich transmembrane protein 2) and KCNQ3 (Potassium voltage-gated channel subfamily KQT member 3).

How many genetic variants are linked to Seizures, benign familial infantile, 3?

926 variants: 183 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 723 are of uncertain significance or have conflicting reports.

Which uncertain variants in Seizures, benign familial infantile, 3 look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SCN2A M1501I and SCN2A M1354V. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Seizures, benign familial infantile, 3?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 181 disease-causing and 75 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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