rs1188425438
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_020822.3(KCNT1):c.2045G>A(p.Arg682Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R682W) has been classified as Uncertain significance.
Frequency
Consequence
NM_020822.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNT1 | NM_020822.3 | c.2045G>A | p.Arg682Gln | missense_variant | 19/31 | ENST00000371757.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNT1 | ENST00000371757.7 | c.2045G>A | p.Arg682Gln | missense_variant | 19/31 | 1 | NM_020822.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000132 AC: 1AN: 76004Hom.: 0 AF XY: 0.0000255 AC XY: 1AN XY: 39190
GnomAD4 exome AF: 0.0000130 AC: 17AN: 1309666Hom.: 0 Cov.: 31 AF XY: 0.0000189 AC XY: 12AN XY: 636522
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 682 of the KCNT1 protein (p.Arg682Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of KCNT1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 447646). 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 with a negative predictive value of 80%. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2023 | The c.2045G>A (p.R682Q) alteration is located in exon 19 (coding exon 19) of the KCNT1 gene. This alteration results from a G to A substitution at nucleotide position 2045, causing the arginine (R) at amino acid position 682 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 25, 2017 | - - |
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