20-63444720-C-T

Position:

• chr20-63444720-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000359125.7(KCNQ2):​c.629G>A​(p.Arg210His) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R210C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 ENST00000359125.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 4.90

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 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000359125.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63444721-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205873.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, 0.903
• PP5: Variant 20-63444720-C-T is Pathogenic according to our data. Variant chr20-63444720-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 279931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63444720-C-T is described in Lovd as [Pathogenic]. Variant chr20-63444720-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.629G>A	p.Arg210His	missense_variant	4/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.629G>A	p.Arg210His	missense_variant	4/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448556 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 7 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 20, 2023	This heterozygous mis-sense variant identified in 1 month female with neonatal onset of seizures from day 1, encephalopathy and abnormal EEG . This variant is absent from gnomAD database [PM2]. Insilico prediction predicts a deleterious nature of this variant, REVEL score: 0.85. Based on the familial segregation is was found to be a “de-novo” variant. There is a clinvar entry [Variation ID: 279931] for this variant with a Pathogenic interpretation by multiple submitters [PP5]. PMID [26446091] -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jul 10, 2019	The p.Arg210His variant has been reported as a de novo change in multiple individuals with epileptic encephalopathy (PMID: 24107868, 24371303, 25880994, 26446091). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The p.Arg210His variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This substitution is predicted to be within the transmembrane segment S4 voltage sensor. Functional studies have demonstrated that the p.Arg210His variant disrupts the normal channel conductance activity of the KCNQ2 protein (PMID: 28283543). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.629G>A (p.Arg210His) variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jul 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with epileptic encephalopathy, early infantile, 7 (MIM#613720). Missense have been reported with a dominant negative mechanism, causing both early infantile epileptic encephalopathy and benign neonatal seizures (OMIM, PMID 24318194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Some variants have been reported with both severe infantile onset epileptic encephalopathy and milder benign seizures (OMIM) (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes (p.Arg210Pro, p.Arg210Cys) have been reported in several de novo patients with infantile onset epileptic encephalopathy (ClinVar, PMID: 25818041). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple de novo patients with infantile onset epileptic encephalopathy (ClinVar, PMID: 24107868, PMID: 24371303, PMID: 26446091). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2018	The R210H pathogenic variant has been reported multiple times as a de novo change in individuals with epileptic encephalopathy (Weckhuysen et al., 2013; Pisano et al., 2015; Reid et al., 2016). The R210H variant is not observed in large population cohorts (Lek et al., 2016). The R210H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, a different missense variant in the same residue (R210C) as well as multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider R210H to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 210 of the KCNQ2 protein (p.Arg210His). 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: 24107868, 24371303, 25880994, 26446091). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 279931). 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: 28283543). For these reasons, this variant has been classified as Pathogenic. -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	.;.;T;T;D;T;D;T;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;L;.;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.5	.;.;.;.;D;.;D;.;D;D;D;.
REVEL	Pathogenic	0.85
Sift	Benign	0.072	.;.;.;.;T;.;T;.;T;D;T;.
Sift4G	Benign	0.11	T;T;T;T;T;.;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.;.
Vest4		0.78
MutPred		0.62		Loss of MoRF binding (P = 0.0537);Loss of MoRF binding (P = 0.0537);Loss of MoRF binding (P = 0.0537);Loss of MoRF binding (P = 0.0537);Loss of MoRF binding (P = 0.0537);.;Loss of MoRF binding (P = 0.0537);.;Loss of MoRF binding (P = 0.0537);Loss of MoRF binding (P = 0.0537);Loss of MoRF binding (P = 0.0537);.;
MVP		0.97
MPC		3.1
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.81
gMVP		0.97

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: rs886041262; hg19: chr20-62076073; COSMIC: COSV60432443; COSMIC: COSV60432443;