chr20-63413471-C-T

Position:

chr20-63413471-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_172107.4(KCNQ2):c.1742G>A(p.Arg581Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R581L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:2

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 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-63413471-C-A is described in Lovd as [Pathogenic].

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, 0.983

PP5

Variant 20-63413471-C-T is Pathogenic according to our data. Variant chr20-63413471-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.1742G>A	p.Arg581Gln	missense_variant	15/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7 linkuse as main transcript	c.1742G>A	p.Arg581Gln	missense_variant	15/17	1	NM_172107.4	ENSP00000352035	A1	O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Seizures, benign familial neonatal, 1

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 04, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2018

The p.R581Q variant (also known as c.1742G>A), located in coding exon 15 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 1742. The arginine at codon 581 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected as de novo in several individuals with early onset encephalopathy and/or clonic spasms and focal seizures (Olson HE et al. Ann. Neurol., 2017 Mar;81:419-429; Meng L et al. JAMA Pediatr, 2017 Dec;171:e173438; Parrini E et al. Hum. Mutat., 2017 Feb;38:216-225). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

ClinVar contains an entry for this variant (Variation ID: 21769). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 27864847, 28133863, 28973083; Invitae). 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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 581 of the KCNQ2 protein (p.Arg581Gln). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg581 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25262651, 29186148). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Epileptic encephalopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2020

Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20437616, 29186148, 25262651, 27864847, 28973083, 29141310, 28133863) -

Complex neurodevelopmental disorder

Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

.;.;D;D;D;T;D;D;.;.;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.76

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

0.98

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

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.3

.;.;.;.;.;.;M;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.023

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.91

.;.;.;.;.;.;Loss of MoRF binding (P = 0.0195);.;.;.;.;

MVP

0.99

MPC

1.8

ClinPred

1.0

GERP RS

5.0

Varity_R

0.95

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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