Variant 20-63413526-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_172107.4(KCNQ2):c.1687G>A(p.Asp563Asn) 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. 12/21 in silico tools predict a damaging 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. D563E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 7.75

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a hotspot region, there are 7 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-63413524-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2855247.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, KCNQ2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

PP5

Variant 20-63413526-C-T is Pathogenic according to our data. Variant chr20-63413526-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 205917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.1687G>A	p.Asp563Asn	missense_variant	15/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7 linkuse as main transcript	c.1687G>A	p.Asp563Asn	missense_variant	15/17	1	NM_172107.4	A1	O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	Published functional studies demonstrate a decrease in PIP2 apparent affinity and a reduction in channel function; reported using alternate nomenclature D535N (Ambrosino et al., 2018); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This substitution is predicted to be within the C-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 24107868, 23621294, 31172278, 25959266, 26007637, 27334371, 29383681, 32581083, 30669290, 32651551) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 27, 2016	- -

Developmental and epileptic encephalopathy, 7

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -
Pathogenic, no assertion criteria provided	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Aug 19, 2022	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2016

The p.D563N pathogenic mutation (also known as c.1687G>A), located in coding exon 15 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 1687. The aspartic acid at codon 563 is replaced by asparagine, an amino acid with highly similar properties. This mutation has been detected as a de novo occurrence with confirmed paternity in three unrelated individuals with neonatal epileptic encephalopathy diagnoses before age one month (Weckhuysen S, et al. Neurology 2013;81(19):1697-703; Milh M, et al. Am. J. Med. Genet. A 2015; 167A(10):2314-8). In addition, a different alteration located at the same position, p.D563E, was detected as a de novo occurrence with confirmed paternity in an individual with early onset epileptic encephalopathy (Kato M, et al. Epilepsia 2013 Jul; 54(7):1282-7). Based on the supporting evidence, p.D563N is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 23, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp563 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23621294, 27334371). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 29383681). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 205917). This variant is also known as D535N. This missense change has been observed in individual(s) with benign familial neonatal seizures (PMID: 24107868, 26007637). 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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 563 of the KCNQ2 protein (p.Asp563Asn). -

Seizures, benign familial neonatal, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center of Excellence for Medical Genomics, Chulalongkorn University

Sep 08, 2002

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.91

Sift4G

Uncertain

0.0030

D;D;D;D;D;.;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;D;.;D;D;.

Vest4

0.99

MutPred

0.72

.;.;.;.;.;.;Gain of MoRF binding (P = 0.0504);.;.;.;.;

MVP

0.96

MPC

1.6

ClinPred

1.0

GERP RS

5.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over