rs118192194

Variant names:

• chr20-63446769-G-A
• rs118192194
• NM_172107.4:c.365C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63446769-G-A
• chr20-63446769-G-C

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• neonatal encephalopathy with non-epileptic myoclonus

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neonatal-onset developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• seizures, benign familial neonatal, 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign neonatal seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to benign familial infantile epilepsy, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, 7, benign familial neonatal-infantile seizures, benign neonatal seizures, neonatal-onset developmental and epileptic encephalopathy, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, seizures, benign familial neonatal, 1, neonatal encephalopathy with non-epileptic myoclonus.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 21787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.365C>T	p.Ser122Leu	missense_variant	Exon 2 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.365C>T	p.Ser122Leu	missense_variant	Exon 2 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 16, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

KCNQ2-related disorder Pathogenic:1

Jun 26, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Developmental and epileptic encephalopathy Pathogenic:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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
DEOGEN2	Benign	0.39	.;.;T;T;D;D;T;.;.;.
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
PhyloP100		7.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.2	.;.;.;.;D;D;.;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	.;.;.;.;D;D;.;D;D;D
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
PromoterAI		-0.0051	Neutral
Varity_R		0.84
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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