9-135779429-G-A
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_020822.3(KCNT1):c.2800G>A(p.Ala934Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A934S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020822.3 missense
Scores
Clinical Significance
Conservation
Publications
- childhood-onset epilepsy syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- developmental and epileptic encephalopathy, 14Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- malignant migrating partial seizures of infancyInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
- autosomal dominant nocturnal frontal lobe epilepsy 5Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- autosomal dominant nocturnal frontal lobe epilepsyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 33 show subpopulations
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74444 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
ClinVar
Submissions by phenotype
not provided Pathogenic:3
- -
KCNT1: PS2, PM1, PM2, PS4:Moderate, PS3:Supporting -
Published functional studies demonstrate a damaging effect as the p.A934T variant causes a marked increase in KCNT1 protein function; the mutant channel activates significantly more quickly than wild-type channels with greater current amplitude (Barcia et al., 2012; Milligan et al., 2014; Kim et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23599387, 26122718, 23086397, 25482562, 27620904, 26785903, 26441003, 26140313, 26740507, 27779742, 27064559, 29390993, 30182498, 31054490, 31487502, 30847371, 30782581, 31872048, 31532509, 32139178, 24591078, 29100083, 32167590) -
Developmental and epileptic encephalopathy, 14 Pathogenic:3
- -
- -
- -
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Pathogenic:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 934 of the KCNT1 protein (p.Ala934Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy, including malignant migrating partial seizures of infancy (PMID: 23086397, 25482562, 26122718, 26140313, 26993267). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39594). 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) indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 23086397, 24591078). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at