rs1057516098

Positions:

• chr20-63439657-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.868G>A​(p.Gly290Ser) 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.98

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a region_of_interest Mediates interaction with SLC5A3 (size 101) in uniprot entity KCNQ2_HUMAN there are 33 pathogenic changes around while only 0 benign (100%) in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.984
• PP5: Variant 20-63439657-C-T is Pathogenic according to our data. Variant chr20-63439657-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 369768.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.868G>A	p.Gly290Ser	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.868G>A	p.Gly290Ser	missense_variant	6/17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	The variant has been previously reported as de novoo in at least two similarly affected unrelated individuals (PMID: 27779742, 23692823, 23621294, PS2, PS4_M). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Gly290Val, p.Gly290Asp) has been reported as pathogenic (ClinVar ID:VCV000523563.1, PMID: 23621294, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.959, 3Cnet: 0.941, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly290 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 24318194). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 369768). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 23621294, 23692823, 27779742). 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 290 of the KCNQ2 protein (p.Gly290Ser). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2017

The G290S variant in the KCNQ2 gene has been reported previously as a de novo change in multiple unrelated individuals with early onset epileptic encephalopathy (Milh et al., 2013; Kato et al., 2013; Zhang et al., 2016). The G290S variant is not observed in large population cohorts (Lek et al., 2016). The G290S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments, and a different missense variant at the same position (G290D) as well as missense variants in nearby residues (T287N, R291G, R291S) have been reported in the Human Gene Mutation Database in association with epileptic encephalopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;D;D;D;T;D;D;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;.;.;.;.;.;H;.;H;H;H
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.5	.;.;.;.;D;.;D;.;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;.;.;.;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		0.91
MutPred		0.87		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.95
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: rs1057516098; hg19: chr20-62071010; COSMIC: COSV60435371; COSMIC: COSV60435371;