rs28939684

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_172107.4(KCNQ2):​c.640C>T​(p.Arg214Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KCNQ2
NM_172107.4 missense

Scores

13
3
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:2

Conservation

PhyloP100: 1.78
Variant links:
Genes affected
KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_172107.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr20-63444708-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 578032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ2. . Gene score misZ 4.0411 (greater than the threshold 3.09). Trascript score misZ 3.6968 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 20-63444709-G-A is Pathogenic according to our data. Variant chr20-63444709-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ2NM_172107.4 linkuse as main transcriptc.640C>T p.Arg214Trp missense_variant 4/17 ENST00000359125.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ2ENST00000359125.7 linkuse as main transcriptc.640C>T p.Arg214Trp missense_variant 4/171 NM_172107.4 A1O43526-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1440890
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
714432
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 27, 2015- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 12, 2022Published functional studies demonstrate a damaging effect: significantly altered channel voltage-dependent gating in homomeric and heteromeric configurations with Q3 by reducing the opening and increasing the closing kinetics and decreasing voltage sensitivity (Castaldo et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 12015163, 16916607, 28488083, 19818940, 14534157, 17475800, 19380078, 18238816, 18353052, 18698150, 11690625, 21687499, 11572947, 28372301, 11784811, 11175290, 29056246, 16686649, 35642783) -
Seizures, benign familial neonatal, 1 Pathogenic:1Other:1
not provided, no classification providedliterature onlyGeneReviews-BFNE (benign familial neonatal epilepsy) -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2000- -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeAug 03, 2023For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg214 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31152295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 11784811). 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 expected to disrupt KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 7385). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 11175290). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 214 of the KCNQ2 protein (p.Arg214Trp). -
Complex neurodevelopmental disorder Other:1
not provided, no classification providedliterature onlyChannelopathy-Associated Epilepsy Research Center-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
.;.;D;D;D;T;D;D;.;.;.;.
Eigen
Benign
-0.056
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;.;.;.;.;.;H;.;H;H;H;.
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-7.2
.;.;.;.;D;.;D;.;D;D;D;.
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
.;.;.;.;D;.;D;.;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;.;D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.;D;.;D;D;.;.
Vest4
0.95
MVP
1.0
MPC
2.8
ClinPred
1.0
D
GERP RS
0.17
Varity_R
0.74
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28939684; hg19: chr20-62076062; API