9-135792051-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_020822.3(KCNT1):c.3598C>T(p.Arg1200Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000891 in 1,604,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_020822.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000145 AC: 22AN: 152146Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000912 AC: 22AN: 241308Hom.: 0 AF XY: 0.000114 AC XY: 15AN XY: 131628
GnomAD4 exome AF: 0.0000833 AC: 121AN: 1451878Hom.: 0 Cov.: 32 AF XY: 0.0000761 AC XY: 55AN XY: 722768
GnomAD4 genome AF: 0.000144 AC: 22AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15AN XY: 74440
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Uncertain:2
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1200 of the KCNT1 protein (p.Arg1200Cys). This variant is present in population databases (rs372028322, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 279822). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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Developmental and epileptic encephalopathy, 14 Uncertain:1
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not provided Uncertain:1
The R1200C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1200C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with KCNT1-related disease (Stenson et al., 2014). Additionally, the R1200C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; but the 1000 Genomes Project reports R1200C was observed in 2/206 (1.0%) alleles from individuals of Gujarati Indian background, indicating it may be a rare (benign) variant in this population. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Autosomal dominant nocturnal frontal lobe epilepsy 5 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at