8-132129996-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_004519.4(KCNQ3):c.1885G>C(p.Val629Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,613,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V629I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

KCNQ3
NM_004519.4 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:6

Conservation

PhyloP100: 7.37

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

seizures, benign familial neonatal, 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
benign familial infantile epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
benign neonatal seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

KCNQ3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4 link	c.1885G>C	p.Val629Leu	missense_variant, splice_region_variant	Exon 15 of 15	ENST00000388996.10	NP_004510.1	O43525-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10 link	c.1885G>C	p.Val629Leu	missense_variant, splice_region_variant	Exon 15 of 15	1	NM_004519.4	ENSP00000373648.3		O43525-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

251010

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000821

AC:

120

AN:

1460932

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

726768

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5180

European-Non Finnish (NFE)

AF:

0.0000962

AC:

107

AN:

1112008

Other (OTH)

AF:

0.0000663

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41486

American (AMR)

AF:

0.000262

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 13, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The V629L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and it was not observed with any significant frequency in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V629L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

CAADphred>15 -

not specified

Uncertain:1

Dec 05, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jan 15, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V629L variant (also known as c.1885G>C) is located in coding exon 15 of the KCNQ3 gene. The valine at codon 629 is replaced by leucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 15. This alteration has been reported in one individual with rolandic epilepsy as well as in one control individual (Bobbili DR et al. Eur. J. Hum. Genet., 2018 02;26:258-264). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Benign neonatal seizures

Uncertain:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 629 of the KCNQ3 protein (p.Val629Leu). This variant is present in population databases (rs185511111, gnomAD 0.01%). This missense change has been observed in individual(s) with rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 206003). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Seizures, benign familial neonatal, 2

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.62

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.;.;.;.

PhyloP100

7.4

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.6

D;.;D;D;.

REVEL

Pathogenic

0.72

Sift

Benign

0.060

T;.;T;T;.

Sift4G

Uncertain

0.046

D;T;T;T;.

Polyphen

0.77

P;.;.;P;.

Vest4

0.59

MVP

0.81

MPC

0.50

ClinPred

0.42

GERP RS

5.7

Varity_R

0.49

gMVP

0.68

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over