rs758152252
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5BS2
The NM_020822.3(KCNT1):c.1067G>A(p.Arg356Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R356W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020822.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNT1 | NM_020822.3 | c.1067G>A | p.Arg356Gln | missense_variant | 12/31 | ENST00000371757.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNT1 | ENST00000371757.7 | c.1067G>A | p.Arg356Gln | missense_variant | 12/31 | 1 | NM_020822.3 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250162Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135586
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460660Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 726598
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2022 | This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. This variant is present in population databases (rs758152252, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 356 of the KCNT1 protein (p.Arg356Gln). ClinVar contains an entry for this variant (Variation ID: 373294). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg356 amino acid residue in KCNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25326635, 31532594; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 02, 2016 | The R356Q variant in the KCNT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R356Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R356Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R356Q as a variant of uncertain significance - |
Developmental and epileptic encephalopathy, 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Autosomal dominant nocturnal frontal lobe epilepsy 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at