9-135772928-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The ENST00000371757.7(KCNT1):āc.2222A>Cā(p.Asp741Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000329 in 1,517,730 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 (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D741G) has been classified as Likely benign.
Frequency
Consequence
ENST00000371757.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNT1 | NM_020822.3 | c.2222A>C | p.Asp741Ala | missense_variant | 19/31 | ENST00000371757.7 | NP_065873.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNT1 | ENST00000371757.7 | c.2222A>C | p.Asp741Ala | missense_variant | 19/31 | 1 | NM_020822.3 | ENSP00000360822 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000794 AC: 1AN: 125992Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67712
GnomAD4 exome AF: 0.00000293 AC: 4AN: 1365674Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1AN XY: 672044
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74270
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 | Labcorp Genetics (formerly Invitae), Labcorp | Feb 17, 2021 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KCNT1-related conditions. While this variant is present in population databases (rs756359375), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces aspartic acid with alanine at codon 741 of the KCNT1 protein (p.Asp741Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at