rs1057516085

Positions:

• chr20-63444747-C-T

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.602G>A​(p.Arg201His) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 7.74

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 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 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, 0.987
• PP5: Variant 20-63444747-C-T is Pathogenic according to our data. Variant chr20-63444747-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 369753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63444747-C-T is described in Lovd as [Pathogenic]. Variant chr20-63444747-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.602G>A	p.Arg201His	missense_variant	4/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.602G>A	p.Arg201His	missense_variant	4/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2020	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 29190809, 28867141, 28139826, 25880994, 27030113, 27535030, 23708187, 25740509) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -

Severe intellectual deficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory of Molecular Genetics, CHU Rennes

-

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2018

For these reasons, this variant has been classified as Pathogenic. The p.Arg201 amino acid residue in KCNQ2 has been determined to be clinically significant (PMID: 28139826, 27535030, 28867141). This suggests that variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change results in a protein that has a significant increase in current density and loss of voltage-dependent gating (PMID: 25740509) This variant has been reported to be de novo in several individuals affected with early infantile epileptic encephalopathy (PMID: 23708187, 25880994, 29190809, 28139826). ClinVar contains an entry for this variant (Variation ID: 369753). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 201 of the KCNQ2 protein (p.Arg201His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

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

-

EE (epileptic encephalopathy) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;.;D;D;D;T;D;D;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.69
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	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	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	-4.5	.;.;.;.;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.97
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		0.90		Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);.;Loss of MoRF binding (P = 0.0112);.;Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);.;
MVP		0.99
MPC		3.1
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.89
gMVP		0.99

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: rs1057516085; hg19: chr20-62076100; COSMIC: COSV100610433; COSMIC: COSV100610433;