rs759258191
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_172107.4(KCNQ2):c.2312C>T(p.Thr771Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000824 in 1,577,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T771T) has been classified as Likely benign.
Frequency
Consequence
NM_172107.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.2312C>T | p.Thr771Ile | missense_variant | 17/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.2312C>T | p.Thr771Ile | missense_variant | 17/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000494 AC: 9AN: 182270Hom.: 0 AF XY: 0.0000298 AC XY: 3AN XY: 100680
GnomAD4 exome AF: 0.00000702 AC: 10AN: 1425344Hom.: 0 Cov.: 36 AF XY: 0.00000566 AC XY: 4AN XY: 706676
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74362
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 771 of the KCNQ2 protein (p.Thr771Ile). This variant is present in population databases (rs759258191, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pyridoxine-responsive epileptic encephalopathy (PMID: 35906921). ClinVar contains an entry for this variant (Variation ID: 461417). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 35104249). 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. - |
Developmental and epileptic encephalopathy, 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Pediatrics, West China Second University Hospital, Sichuan University | Dec 31, 2019 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Complex neurodevelopmental disorder Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at