20-63444748-G-A

Position:

• chr20-63444748-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 ENST00000359125.7(KCNQ2):​c.601C>T​(p.Arg201Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 ENST00000359125.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1 O:2
• Conservation: PhyloP100: 1.17

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 hotspot region, there are 14 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 chr20-63444748-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1992305.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, 0.985
• PP5: Variant 20-63444748-G-A is Pathogenic according to our data. Variant chr20-63444748-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 205869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63444748-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.601C>T	p.Arg201Cys	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.601C>T	p.Arg201Cys	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: 1453118 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721920

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:12 Uncertain:1 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	NeuroMeGen, Hospital Clinico Santiago de Compostela	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.601C>T (p.Arg201Cys) in the KCNQ2 gene has been reported in heterozygous state in an individual affected with early onset epileptic encephalopathy (Hortigüela M. et al., 2017). Experimental studies have shown that this missense change stabilized the activated state of the channel, thereby producing gain-of function (Miceli F. et al., 2015). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes databases. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Uncertain Significance. The amino acid Arginine at position 201 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000205869, PMID:24107868). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27535030). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000369753, PMID:23708187). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.931>=0.6, 3CNET: 0.997>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Aug 19, 2022	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Pathogenic, for Epileptic encephalopathy, early infantile, 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. Loss of voltage-dependent channel gating and increased channel activation, gain-of-function mutation (PMID:25740509). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation (PMID:26993267,28133863,24107868,28687180). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28687180). -

Seizures, benign familial neonatal, 1 Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Sep 08, 2002	- -
Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it once in our laboratory de novo in a 6-month-old female with motor delays, hypotonia, epilepsy (clinically thought to be early infantile myoclonic encephalopathy, onset at day 2 of life, with apneic episodes, controlled by medication but with onset of myoclous), nystagmus -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2021	Published functional studies demonstrate a gain-of-function (Miceli et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 28687180, 25740509, 27535030, 28133863, 28867141, 24107868, 28139826, 32917465) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the KCNQ2 protein (p.Arg201Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 24107868, 27535030, 28133863, 28687180). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205869). 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: 25740509). This variant disrupts the p.Arg201 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23708187, 25880994, 28139826, 29190809). 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. -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;.;D;D;D;T;D;D;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	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	0.92	D
PROVEAN	Pathogenic	-7.2	.;.;.;.;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;.;.;.;D;.;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		0.98
MutPred		0.89		Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);.;Loss of MoRF binding (P = 0.0037);.;Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);.;
MVP		1.0
MPC		3.3
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs796052623; hg19: chr20-62076101;