rs1801475

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_172107.4(KCNQ2):c.2339A>C(p.Asn780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,604,550 control chromosomes in the GnomAD database, including 328,384 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 27470 hom., cov: 35)

Exomes 𝑓: 0.64 ( 300914 hom. )

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:2

Conservation

PhyloP100: 1.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=7.1157156E-6).

BP6

Variant 20-63406924-T-G is Benign according to our data. Variant chr20-63406924-T-G is described in ClinVar as [Benign]. Clinvar id is 21779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63406924-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4 link	c.2339A>C	p.Asn780Thr	missense_variant	Exon 17 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.2339A>C	p.Asn780Thr	missense_variant	Exon 17 of 17	1	NM_172107.4	ENSP00000352035.2		O43526-1

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

90517

AN:

152022

Hom.:

27458

Cov.:

show subpopulations

Gnomad AFR

AF:

0.497

Gnomad AMI

AF:

0.647

Gnomad AMR

AF:

0.557

Gnomad ASJ

AF:

0.496

Gnomad EAS

AF:

0.638

Gnomad SAS

AF:

0.619

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.655

Gnomad OTH

AF:

0.588

GnomAD3 exomes

AF:

0.609

AC:

140836

AN:

231186

Hom.:

43252

AF XY:

0.614

AC XY:

77931

AN XY:

126864

show subpopulations

Gnomad AFR exome

AF:

0.495

Gnomad AMR exome

AF:

0.511

Gnomad ASJ exome

AF:

0.496

Gnomad EAS exome

AF:

0.623

Gnomad SAS exome

AF:

0.609

Gnomad FIN exome

AF:

0.654

Gnomad NFE exome

AF:

0.657

Gnomad OTH exome

AF:

0.624

GnomAD4 exome

AF:

0.642

AC:

931932

AN:

1452412

Hom.:

300914

Cov.:

AF XY:

0.640

AC XY:

462208

AN XY:

722134

show subpopulations

Gnomad4 AFR exome

AF:

0.490

Gnomad4 AMR exome

AF:

0.519

Gnomad4 ASJ exome

AF:

0.485

Gnomad4 EAS exome

AF:

0.639

Gnomad4 SAS exome

AF:

0.598

Gnomad4 FIN exome

AF:

0.657

Gnomad4 NFE exome

AF:

0.659

Gnomad4 OTH exome

AF:

0.615

GnomAD4 genome

AF:

0.595

AC:

90562

AN:

152138

Hom.:

27470

Cov.:

AF XY:

0.598

AC XY:

44509

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.497

Gnomad4 AMR

AF:

0.556

Gnomad4 ASJ

AF:

0.496

Gnomad4 EAS

AF:

0.639

Gnomad4 SAS

AF:

0.617

Gnomad4 FIN

AF:

0.652

Gnomad4 NFE

AF:

0.655

Gnomad4 OTH

AF:

0.583

Alfa

AF:

0.639

Hom.:

34024

Bravo

AF:

0.578

TwinsUK

AF:

0.662

AC:

2454

ALSPAC

AF:

0.658

AC:

2535

ESP6500AA

AF:

0.510

AC:

2225

ESP6500EA

AF:

0.644

AC:

5527

ExAC

AF:

0.604

AC:

72439

Asia WGS

AF:

0.613

AC:

2128

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 18, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 80. Only high quality variants are reported. -

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizures, benign familial neonatal, 1

Benign:2Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 28, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28038823) -

Inborn genetic diseases

Benign:1

Dec 31, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 7

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign

0.060

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

9.5

DANN

Benign

0.47

DEOGEN2

Benign

0.0034

.;T;T;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.0088

T;T;T;T;T;T

MetaRNN

Benign

0.0000071

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

.;.;N;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.61

.;.;N;.;N;.

REVEL

Benign

0.082

Sift

Benign

0.43

.;.;T;.;T;.

Sift4G

Benign

0.54

T;.;T;T;T;T

Polyphen

0.0

B;.;B;.;B;B

Vest4

0.041

MPC

0.64

ClinPred

0.00066

GERP RS

0.092

Varity_R

0.040

gMVP

0.18

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