rs118192194

chr20-63446769-G-A

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.365C>T(p.Ser122Leu) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S122S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.79

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNQ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 20-63446769-G-A is Pathogenic according to our data. Variant chr20-63446769-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63446769-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.365C>T	p.Ser122Leu	missense_variant	2/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.365C>T	p.Ser122Leu	missense_variant	2/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2022	Published functional studies demonstrate slowed activation kinetics of the voltage-gated channel (Hunter et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the extracellular loop between the S1 and S2 transmembrane segments; This variant is associated with the following publications: (PMID: 33098118, 16916607, 18238816, 28074849, 28082013, 27602407, 18698150, 28488083, 26544041, 34070668, 34711204, 33659638) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

KCNQ2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 26, 2019

The KCNQ2 c.365C>T (p.Ser122Leu) variant is a missense variant that has been reported in three studies, in which it is found in a heterozygous state in a total of six individuals, of whom three are unrelated (Hunter et al. 2006; Zhang et al. 2015; Millichap et al. 2016). One individual had early onset epileptic encephalopathy and five had benign familial neonatal seizures (BFNS). The p.Ser122Leu variant was found in a father with BNFS and his two affected sons, but was absent from three unaffected family members (Hunter et al. 2006). Additionally, a pair of siblings with BFNS were found to be heterozygous for the variant, but parental testing was not performed (Millichap et al. 2016). The variant was absent from 400 control subjects and is not found in the Genome Aggregation Database despite being in a region of good sequence coverage, so the variant is presumed to be rare. Electrophysiology studies were performed in Xenopus oocytes to assess the effect of the p.Ser122Leu variant. A shift in voltage dependence of activation was observed resulting in reduction of activation kinetics when compared to wild type (Hunter et al. 2006). Based on the collective evidence and the application of ACMG criteria, the p.Ser122Leu variant is classified as pathogenic for KCNQ2-related disorders. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 122 of the KCNQ2 protein (p.Ser122Leu). 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: 16916607, 26544041, 27602407). 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: 21787). 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: 16916607). For these reasons, this variant has been classified as Pathogenic. -

Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.S122L in KCNQ2 (NM_172107.4) has been previously reported in heterozygous state in affected indviduals with both epileptic encephalopathy and benign neonatal seizures (Zhang Y et al, Millichap J et al). Experimental studies show slower electrophysiological activation as compared to wild type (Hunter J et al). The variant has been deposited to ClinVar as Pathogenic. The p.S122L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.S122L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.365 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -

Seizures, benign familial neonatal, 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

BFNE (benign familial neonatal epilepsy). FS (febrile seizures) in later life; seizures until 7 years. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;M;.;M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.79	T
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;T
Polyphen		0.99	D;.;.;.;.;D;.;D;D;.
Vest4		0.92
MutPred		0.80		Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);.;Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.84
gMVP		0.94

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: rs118192194; hg19: chr20-62078122; COSMIC: COSV60435046; COSMIC: COSV60435046;