20-63439704-G-A

Position:

• chr20-63439704-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000359125.7(KCNQ2):​c.821C>T​(p.Thr274Met) 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. 13/21 in silico tools predict a damaging 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. T274S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 ENST00000359125.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:2
• Conservation: PhyloP100: 9.77

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 17 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr20-63439705-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3236070.Status of the report is criteria_provided_single_submitter, 1 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, 0.93
• PP5: Variant 20-63439704-G-A is Pathogenic according to our data. Variant chr20-63439704-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 167208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63439704-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.821C>T	p.Thr274Met	missense_variant	6/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.821C>T	p.Thr274Met	missense_variant	6/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Aug 17, 2023	This sequence variant is a single nucleotide substitution (C>T) at position 821 of the coding sequence of the KCNQ2 gene that results in a threonine to methionine amino acid change at residue 274 of the potassium voltage-gated channel subfamily Q member 2 protein. The 274 residue falls in a pore-forming domain (Uniprot) which plays a critical role in the regulation of neurol excitability mediated by KCNQ2. This is a de novo, previously reported variant (ClinVar 167208) that has been observed in the literature in many individuals affected by epileptic seizures (PMID: 2753503, 30776697, 31780880, 34711204). This variant is absent from the gnomAD population database (0 of ~250,000 alleles). Bioinformatic tools predict that this amino acid change would be damaging, and the Thr274 residue is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant confirms a significant reduction in conductance through this voltage-gated potassium channel protein (PMID: 24318194, PMID: 33336127). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM1, PM2, PP2, PP3, PS2, PS3, PS4 -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 19, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been previously reported as de novo in a similarly affected individual (PMID: 22275249, 27535030, PS2_S). It has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 22275249, 27535030, 27779742, 28133863, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24318194, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, PP3_P). A missense variant is a common mechanism associated with Epileptic encephalopathy (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Aug 11, 2014	- -
Pathogenic, no assertion criteria provided	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Aug 19, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	Published functional studies demonstrate a damaging effect, as current amplitudes of homotetramers and heterotetramers were reduced (Orhan et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22275249, 29056246, 28133863, 27779742, 31273778, 20437616, 27602407, 23692823, 25960349, 28488083, 30776697, 27535030, 31780880, 33041849, 32239694, 33822359, 34055682, 33098118, 31175295, 31440721, 35217970, 24318194) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2018	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 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: 167208). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 22275249, 27535030, 27779742, 28133863). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 274 of the KCNQ2 protein (p.Thr274Met). -

Seizures, benign familial neonatal, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center of Excellence for Medical Genomics, Chulalongkorn University

Sep 08, 2002

- -

West syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Dec 15, 2023

- -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;.;D;D;D;D;D;D;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;.;.;.;.;.;H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	.;.;.;.;D;.;D;.;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.98
MutPred		0.67		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.94
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

Other links and lift over

dbSNP: rs727503974; hg19: chr20-62071057; COSMIC: COSV60435951; COSMIC: COSV60435951;