20-63444756-C-T

Variant names:

• chr20-63444756-C-T
• rs796052621
• NM_172107.4:c.593G>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.593G>A​(p.Arg198Gln) 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:10 O:1
• Conservation: PhyloP100: 5.97

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 transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 22) in uniprot entity KCNQ2_HUMAN there are 15 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 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 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, 0.956
• PP5: Variant 20-63444756-C-T is Pathogenic according to our data. Variant chr20-63444756-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 205867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63444756-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.593G>A	p.Arg198Gln	missense_variant	Exon 4 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.593G>A	p.Arg198Gln	missense_variant	Exon 4 of 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:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 7 Pathogenic:4

Apr 05, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 18, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS3_MOD,PM1,PM2_SUP,PP3 -

Apr 09, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Missense variants have been shown to have gain of function effects, whilst many NMD-predicted variants with loss of function effects have been reported (PMID 24318194; ClinVar). (N) 0104 - Dominant Negative is a mechanism of disease for this gene (PMID 24318194). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a glutamine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Ion transport domain). (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported de novo in individuals with infantile spasms without prior neonatal seizures (ClinVar; PMID 27861786). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies with this variant showed gain of function effects on channel function (PMID 27861786). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:2

Sep 28, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the R198Q substitution alters voltage gating of the channel (Miceli et al., 2008; Millichap et al., 2016); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18515377, 31965297, 29655203, 31440733, 27861786, 29390993, 32506321, 29129156, 29455050, 33951346, 34163418, 31440721) -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 13, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Sep 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 205867). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 198 of the KCNQ2 protein (p.Arg198Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epilepsy in infancy (PMID: 27861786, 29390993). In at least one individual the variant was observed to be de novo. 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: 27861786). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Apr 26, 2021

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1_strong;PP5_strong;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting -

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

Nov 11, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ2 NM_172107.3 exon 4 p.Arg198Gln (c.593G>A): This variant has been reported in the literature as de novo in at least 4 individuals with infantile spasms and hypsarrhythmia (Millichap 2017 PMID:27861786). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:205867). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, splice prediction tools strongly predict the creation of a new acceptor site; however, further studies are needed to understand its impact. Functional studies also support this variant may impact the protein, potentially creating a gain of function (Millichap 2017 PMID:27861786). In summary, this variant is classified as pathogenic. -

Complex neurodevelopmental disorder Other:1

-

Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	.;.;T;T;D;T;D;T;.;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;M;.;M;M;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	.;.;.;.;D;.;D;.;D;D;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	.;.;.;.;D;.;D;.;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		0.77	P;.;.;.;.;.;D;.;P;P;.;.
Vest4		0.98
MutPred		0.84		Loss of methylation at R198 (P = 0.0098);Loss of methylation at R198 (P = 0.0098);Loss of methylation at R198 (P = 0.0098);Loss of methylation at R198 (P = 0.0098);Loss of methylation at R198 (P = 0.0098);.;Loss of methylation at R198 (P = 0.0098);.;Loss of methylation at R198 (P = 0.0098);Loss of methylation at R198 (P = 0.0098);Loss of methylation at R198 (P = 0.0098);.;
MVP		1.0
MPC		2.4
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.91
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs796052621; hg19: chr20-62076109; COSMIC: COSV60437358; COSMIC: COSV60437358;