20-63444711-C-T

Position:

chr20-63444711-C-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The ENST00000359125.7(KCNQ2):c.638G>A(p.Arg213Gln) variant causes a missense change involving the alteration of a 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNQ2
ENST00000359125.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

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 21 ACMG points.

PS1

Transcript ENST00000359125.7 (KCNQ2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 16 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 chr20-63444711-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685899.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, 0.981

PP5

Variant 20-63444711-C-T is Pathogenic according to our data. Variant chr20-63444711-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.638G>A	p.Arg213Gln	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.638G>A	p.Arg213Gln	missense_variant	4/17	1	NM_172107.4	ENSP00000352035	A1	O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442488

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715338

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 7

Pathogenic:3Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 15, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Aug 10, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS3_Moderate+PP2+PS4_Supporting+PP4+PS2_Supporting+PM5 -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2017

The p.R213Q variant (also known as c.638G>A), located in coding exon 4 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 638. The arginine at codon 213 is replaced by glutamine, an amino acid with highly similar properties. This variant was identified in a 3-year-old female with a history of tremors in utero with seizure onset on day two of life, psychomotor impairment, spastic quadriplegia, and dysmorphic features; her father was mosaic for this alteration and had a history of benign neonatal seizures, tonic-clonic seizures, and myokymia (Weckhuysen S et al. Ann. Neurol., 2012 Jan;71:15-25). This variant also occurred de novo in an individual with early infantile epileptic encephalopathy; however, it is not clear if paternity was confirmed (Trump N et al. J. Med. Genet., 2016 May;53:310-7). In addition, expression of this alteration in CHO cells and Xenopus oocytes showed a decrease in channel voltage sensitivity and large shifts in voltage-dependent activation, respectively (Miceli F et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Mar;110:4386-91; Orhan G et al. Ann. Neurol., 2014 Mar;75:382-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg213 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18353052, 23440208). 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: 22455920, 23440208, 24318194). 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: 39760). This missense change has been observed in individuals with early infantile epileptic encephalopathy (PMID: 22275249, 26993267). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 213 of the KCNQ2 protein (p.Arg213Gln). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2018

p.Arg213Gln (CGG>CAG): c.638 G>A in exon 4 of the KCNQ2 gene (NM_172107.2)The Arg213Gln mutation in the KCNQ2 gene has been reported previously in association with neonatal epileptic encephalopathy (Weckhuysen et al., 2012). This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged Glutamine residue It alters a highly conserved position in the S4 (voltage sensor) segment of the protein, and a different amino acid substitution at the same position (Arg213Trp) has been reported in association with benign familial neonatal seizures (Sadewa et al., 2007). The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.6

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

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.97

MutPred

0.89

Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);.;Loss of MoRF binding (P = 0.0622);.;Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);Loss of MoRF binding (P = 0.0622);.;

MVP

0.98

MPC

3.0

ClinPred

1.0

GERP RS

4.0

Varity_R

0.86

gMVP

0.98

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