chr20-63444729-C-T

Position:

chr20-63444729-C-T

Variant summary

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

The ENST00000359125.7(KCNQ2):c.620G>A(p.Arg207Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNQ2
ENST00000359125.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:2

Conservation

PhyloP100: 7.74

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]

KCNQ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000359125.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-63444730-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7386.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, 0.99

PP5

Variant 20-63444729-C-T is Pathogenic according to our data. Variant chr20-63444729-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63444729-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.620G>A	p.Arg207Gln	missense_variant	4/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7 linkuse as main transcript	c.620G>A	p.Arg207Gln	missense_variant	4/17	1	NM_172107.4	ENSP00000352035	A1	O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451256

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720834

show subpopulations

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2022	Previously reported in an individual with myokymia due to peripheral nerve hyperexcitability, and functional studies indicate this variant alters voltage-dependent activation (Wuttke et al., 2007; Miceli et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17872363, 29655203, 22455920, 32184343, 25959266, 25741868, 24375629, 22169383, 11572947, 32884139, 32506321, 33098118) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 08, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/270462 chr). Predicted to have a damaging effect on the protein. One de novo case with parental identity confirmed. -

KCNQ2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The KCNQ2 c.620G>A variant is predicted to result in the amino acid substitution p.Arg207Gln. This variant has been reported in several individuals with KCNQ2-related phenotypes (Wuttke et al 2007. PubMed ID: 17872363; Lindy AS et al 2018. PubMed ID: 29655203; Camelo CG et al 2020. PubMed ID: 32184343; Sandoval Karamian AG et al 2020. PubMed ID: 33098118). This variant has not been reported in a large population database, indicating it is rare. This variant modifies a charged residue in the ion channel S4 voltage sensor. Variants of this type, including a different missense variant at the same position (p.Arg207Trp), have been associated with disease (Dedek et al. 2001. PubMed ID: 11572947), and both p.Arg207 missense variants change the biochemical properties of the ion channel in vitro (Miceli F et al 2012. PubMed ID: 22455920). Taken together, the c.620G>A (p.Arg207Gln) variant is interpreted as pathogenic. -

Seizures, benign familial neonatal, 1, and/or myokymia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 27, 2007

- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2023

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the KCNQ2 protein (p.Arg207Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 17872363, 25959266, 29655203, 32184343, 34711204). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7391). 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. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 17872363, 22455920). This variant disrupts the p.Arg207 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11572947, 22169383, 22455920, 24375629). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Complex neurodevelopmental disorder

Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

- -

Developmental and epileptic encephalopathy, 7

Other:1

not provided, no classification provided

literature only

GeneReviews

Myokymia, EE (epileptic encephalopathy) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

.;.;D;D;D;T;D;D;.;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.;.;.;.;.;M;.;M;M;M;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.6

.;.;.;.;D;.;D;.;D;D;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

.;.;.;.;D;.;D;.;D;D;D;.

Sift4G

Uncertain

0.058

T;T;D;D;D;.;T;T;T;T;T;T

Polyphen

1.0

D;.;.;.;.;.;D;.;D;D;.;.

Vest4

0.99

MutPred

0.97

Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);.;Loss of MoRF binding (P = 0.0655);.;Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);.;

MVP

1.0

MPC

3.0

ClinPred

1.0

GERP RS

4.0

Varity_R

0.96

gMVP

1.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over