Cognitive impairment with or without cerebellar ataxia: genes and variants

Genes linked to Cognitive impairment with or without cerebellar ataxia

• 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.

  22 disease-causing and 40 uncertain variants in SCN8A are linked to Cognitive impairment with or without cerebellar ataxia.

Where Cognitive impairment with or without cerebellar ataxia variants cluster

• SCN8A S4 of repeat II (positions 840–857): 3 of 22 disease-causing changes, 15.0× more than its size predicts.
• SCN8A Cytoplasmic (positions 235–253): 3 of 22 disease-causing changes, 14.2× more than its size predicts.

Known disease-causing variants in Cognitive impairment with or without cerebellar ataxia

Which prediction tools work for Cognitive impairment with or without cerebellar ataxia

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

• AlphaMissense: 91 out of 100
• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• ESM1b (LLR): 86 out of 100
• PolyPhen-2: 72 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 58 out of 100

Same protein, different disease

• Early-infantile DEE is also caused by SCN8A variants; they fall mostly in different places as the Cognitive impairment with or without cerebellar ataxia variants (90 disease-causing).
• Seizures, benign familial infantile, 3 is also caused by SCN8A variants; they fall mostly in different places as the Cognitive impairment with or without cerebellar ataxia variants (12 disease-causing).
• Complex neurodevelopmental disorder is also caused by SCN8A variants; they fall mostly in different places as the Cognitive impairment with or without cerebellar ataxia variants (8 disease-causing).
• Autosomal recessive inheritance is also caused by SCN8A variants; they fall mostly in different places as the Cognitive impairment with or without cerebellar ataxia variants (3 disease-causing).

Diseases related to Cognitive impairment with or without cerebellar ataxia

• Early-infantile DEE, also linked to SCN8A
• Seizures, benign familial infantile, 3, also linked to SCN8A
• Amyotrophic lateral sclerosis, also linked to SCN8A
• Cardiac arrhythmia, also linked to SCN8A
• Complex neurodevelopmental disorder, also linked to SCN8A
• Epilepsy, also linked to SCN8A
• Fetal akinesia deformation sequence, also linked to SCN8A
• Infantile spasms, also linked to SCN8A
• Genetic developmental and epileptic encephalopathy, also linked to SCN8A
• Cerebellar ataxia, also linked to SCN8A
• Myoclonus, familial, 2, also linked to SCN8A
• Arthrogryposis multiplex congenita, also linked to SCN8A

Frequently asked questions

Which genes are linked to Cognitive impairment with or without cerebellar ataxia?

In CATVariant, Cognitive impairment with or without cerebellar ataxia is linked to 1 analyzed protein: SCN8A (Sodium channel protein type 8 subunit alpha).

How many genetic variants are linked to Cognitive impairment with or without cerebellar ataxia?

62 variants: 22 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 40 are of uncertain significance or have conflicting reports.

Which uncertain variants in Cognitive impairment with or without cerebellar ataxia look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Cognitive impairment with or without cerebellar ataxia?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 22 disease-causing and 35 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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