chr20-63444712-G-A

Position:

• chr20-63444712-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.637C>T​(p.Arg213Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R213Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 6.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 22) in uniprot entity KCNQ2_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• 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 20-63444712-G-A is Pathogenic according to our data. Variant chr20-63444712-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21795.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	c.637C>T	p.Arg213Trp	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	c.637C>T	p.Arg213Trp	missense_variant	4/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444802 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716744

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

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2023	Published functional studies demonstrate that R213W decreases the stability of the ion channel and decreases voltage sensitivity (Miceli et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20437616, 24375629, 24318194, 22455920, 18353052, 29056246, 28038823, 27535030, 26993267, 25959266, 28717674, 27779742, 17765802, 22275249, 32139178, 31512412, 32917465, 32712949, 33726816, 31440721, 33659638, 31440733, 30440138, 23440208) -

Developmental and epileptic encephalopathy, 7 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Feb 02, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	BFNE (benign familial neonatal epilepsy), EE (epileptic encephalopathy) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 19, 2020	This variant was identified as de novo (maternity and paternity confirmed). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2019

The p.R213W pathogenic mutation (also known as c.637C>T), located in coding exon 4 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 637. The arginine at codon 213 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was detected in two siblings with BFNC (benign familial neonatal convulsions). Neither parent carried the mutation, and after parental relationships were confirmed, authors suspected germline mosaicism (Sadewa AH et al. Pediatr Int, 2008 Apr;50:167-71). In another study, this mutation was detected in an individual with EOEE (early onset epileptic encephalopathy) and was found to be mosaic in a parent (Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). In addition, this mutation has been detected in individuals with: non-specific epileptic encephalopathy, neonatal seizure disorder, congenital variant of Rett syndrome, and EIMFS (Epilepsy of Infancy with Migrating Focal Seizures) (Butler KM et al. Pediatr. Neurol., 2017 Dec;77:61-66; Zhang Q et al. Clin. Genet., 2017 May;91:717-724; Wang J et al. Mol Genet Genomic Med, 2019 Sep;:e968; Ware TL et al. Epilepsia Open, 2019 Sep;4:504-510). One functional study showed that this mutation destabilized the potassium ion channel and decreased voltage sensitivity (Miceli F et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Mar;110:4386-91). In addition, a different alteration located at the same position, p.R213Q, has been detected in multiple individuals with epilepsy (Weckhuysen S et al. Ann. Neurol., 2012 Jan;71:15-25; Trump N et al. J. Med. Genet., 2016 May;53:310-7) and has been shown to result in a decrease in channel voltage sensitivity (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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 213 of the KCNQ2 protein (p.Arg213Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with benign familial neonatal seizures or early-onset epilepsy (PMID: 18353052, 27779742, 29056246). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21795). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 23440208). 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: 22275249, 25982755). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Seizures, benign familial neonatal, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;.;D;D;D;T;D;D;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.;.;H;.;H;H;H;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.2	.;.;.;.;D;.;D;.;D;D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.;.
Vest4		0.98
MutPred		0.94		Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);.;Loss of solvent accessibility (P = 0.086);.;Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);.;
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.87
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

Other links and lift over

dbSNP: rs118192203; hg19: chr20-62076065;