20-63413551-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_172107.4(KCNQ2):c.1662G>T(p.Lys554Asn) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K554K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:4

Conservation

PhyloP100: 2.65

Publications

13 publications found

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 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

KCNQ2 links:

LOC105372724 (HGNC:):

LOC105372724 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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, 9 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, 0.958

PP5

Variant 20-63413551-C-A is Pathogenic according to our data. Variant chr20-63413551-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 7388.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4 link	c.1662G>T	p.Lys554Asn	missense_variant	Exon 15 of 17	ENST00000359125.7	NP_742105.1	O43526-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7 link	c.1662G>T	p.Lys554Asn	missense_variant	Exon 15 of 17	1	NM_172107.4	ENSP00000352035.2		O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Seizures, benign familial neonatal, 1

Pathogenic:1

Jul 13, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Seizures, benign familial neonatal, 2

Pathogenic:1

Mar 31, 2016

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Uncertain severity. 2/4 therapy-resistant seizures and intellectual disability. -

not provided

Pathogenic:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNQ2: PS3, PM2, PS4:Moderate, PP2, PP3, PP4 -

Developmental and epileptic encephalopathy, 7

Pathogenic:1

Jul 13, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

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

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.4

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

PhyloP100

2.6

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-4.3

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

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.017

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

Polyphen

1.0

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

Vest4

0.83

MutPred

0.86

.;.;.;.;.;.;Loss of methylation at K554 (P = 0.0085);.;.;.;.;

MVP

0.96

MPC

1.7

ClinPred

0.99

GERP RS

5.0

Varity_R

0.92

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over