8-132129419-T-C

Position:

chr8-132129419-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004519.4(KCNQ3):c.2462A>G(p.Asn821Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

KCNQ3
NM_004519.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: -0.398

Variant links:

Genes affected

KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

KCNQ3 links:

KCNQ3 (HGNC:):

KCNQ3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08496639).

BP6

Variant 8-132129419-T-C is Benign according to our data. Variant chr8-132129419-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21412.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, not_provided=1, Benign=2}.

BS2

High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ3	NM_004519.4 linkuse as main transcript	c.2462A>G	p.Asn821Ser	missense_variant	15/15	ENST00000388996.10	NP_004510.1	O43525-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10 linkuse as main transcript	c.2462A>G	p.Asn821Ser	missense_variant	15/15	1	NM_004519.4	ENSP00000373648.3		O43525-1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251326

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000149

AC:

218

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000464

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000980

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000230

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000238

Hom.:

Bravo

AF:

0.000408

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	KCNQ3: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	This variant is associated with the following publications: (PMID: 20437616, 16235065, 18698150, 17765802) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -

Benign neonatal seizures

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2018

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. -

Benign Neonatal Epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Seizures, benign familial neonatal, 2

Other:1

not provided, no classification provided

literature only

GeneReviews

Found in a typical family with BFNE who also had a KCNQ2 deletion/insertion (likely pathogenic); the KCNQ3 variant does not cosegregate with the disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.8

DANN

Benign

0.22

DEOGEN2

Benign

0.20

T;.;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.76

T;T;T;T;T

M_CAP

Benign

0.0060

MetaRNN

Benign

0.085

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

N;.;.;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

0.40

N;.;N;N;.

REVEL

Benign

0.032

Sift

Benign

1.0

T;.;T;T;.

Sift4G

Benign

1.0

T;T;T;T;.

Polyphen

0.0

B;.;.;B;.

Vest4

0.0090

MVP

0.26

MPC

0.077

ClinPred

0.0023

GERP RS

-0.17

Varity_R

0.026

gMVP

0.088

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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