rs745463637
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_004519.4(KCNQ3):c.1552G>A(p.Ala518Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,446,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
KCNQ3
NM_004519.4 missense
NM_004519.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 4.66
Genes affected
KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3749677).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ3 | NM_004519.4 | c.1552G>A | p.Ala518Thr | missense_variant | 11/15 | ENST00000388996.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ3 | ENST00000388996.10 | c.1552G>A | p.Ala518Thr | missense_variant | 11/15 | 1 | NM_004519.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000171 AC: 4AN: 234246Hom.: 0 AF XY: 0.0000238 AC XY: 3AN XY: 126042
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GnomAD4 exome AF: 0.0000124 AC: 18AN: 1446316Hom.: 0 Cov.: 30 AF XY: 0.0000167 AC XY: 12AN XY: 718118
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Seizures, benign familial neonatal, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | - | A heterozygous missense variation in exon 11 of the KCNQ3 gene that results in the amino acid substitution of Threonine for Alanine at codon 518 was detected . This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant is damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 09, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 10, 2016 | - - |
Benign neonatal seizures Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 18, 2023 | 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. 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 KCNQ3 protein function. ClinVar contains an entry for this variant (Variation ID: 447643). This variant has not been reported in the literature in individuals affected with KCNQ3-related conditions. 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 sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 518 of the KCNQ3 protein (p.Ala518Thr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N;N;.
REVEL
Uncertain
Sift
Benign
T;.;T;T;.
Sift4G
Benign
T;T;T;T;.
Polyphen
B;.;.;B;.
Vest4
MutPred
Loss of ubiquitination at K516 (P = 0.1264);.;.;Loss of ubiquitination at K516 (P = 0.1264);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at