20-63408430-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_172107.4(KCNQ2):c.1870G>A(p.Gly624Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,608,654 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G624W) has been classified as Uncertain significance.
Frequency
Consequence
NM_172107.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.1870G>A | p.Gly624Arg | missense_variant | 16/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.1870G>A | p.Gly624Arg | missense_variant | 16/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000125 AC: 3AN: 239708Hom.: 0 AF XY: 0.00000764 AC XY: 1AN XY: 130848
GnomAD4 exome AF: 0.00000687 AC: 10AN: 1456464Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3AN XY: 724474
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
KCNQ2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 11, 2023 | The KCNQ2 c.1870G>A variant is predicted to result in the amino acid substitution p.Gly624Arg. This variant was reported in an individual with alternating hemiplegia of childhood; however, this individual carried additional candidate variants of uncertain significance, and the KCNQ2 variant was inherited from an unaffected father and absent from an affected sibling (Pavone et al. 2022. PubMed ID: 35177115). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-62039783-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 624 of the KCNQ2 protein (p.Gly624Arg). This variant is present in population databases (rs771211103, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 580776). 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 disruptive. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at