chr8-132480484-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004519.4(KCNQ3):c.49G>A(p.Asp17Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,201,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

KCNQ3
NM_004519.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.552

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17443812).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004519.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.49G>A	p.Asp17Asn	missense	Exon 1 of 15	NP_004510.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.49G>A	p.Asp17Asn	missense	Exon 1 of 15	ENSP00000373648.3
KCNQ3	ENST00000519445.5	TSL:5	c.49G>A	p.Asp17Asn	missense	Exon 1 of 15	ENSP00000428790.1
KCNQ3	ENST00000519589.1	TSL:2	n.-174G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000334

AC:

AN:

149564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000190

AC:

AN:

1051726

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

502370

show subpopulations

African (AFR)

AF:

0.0000473

AC:

AN:

21144

American (AMR)

AF:

0.00

AC:

AN:

7066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11982

East Asian (EAS)

AF:

0.00

AC:

AN:

22130

South Asian (SAS)

AF:

0.00

AC:

AN:

20372

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2820

European-Non Finnish (NFE)

AF:

0.0000177

AC:

AN:

905980

Other (OTH)

AF:

0.0000737

AC:

AN:

40730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.0000334

AC:

AN:

149564

Hom.:

Cov.:

AF XY:

0.0000548

AC XY:

AN XY:

72948

show subpopulations

African (AFR)

AF:

0.0000974

AC:

AN:

41088

American (AMR)

AF:

0.00

AC:

AN:

15030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3424

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67076

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Benign neonatal seizures

Uncertain:1

Nov 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 17 of the KCNQ3 protein (p.Asp17Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KCNQ3-related conditions. ClinVar contains an entry for this variant (Variation ID: 538548). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ3 protein function. 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.17

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

0.0

PhyloP100

0.55

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.54

REVEL

Uncertain

0.33

Sift

Benign

0.067

Sift4G

Benign

0.46

Polyphen

0.050

Vest4

0.25

MutPred

0.21

Gain of MoRF binding (P = 0.0563)

MVP

0.67

MPC

0.89

ClinPred

0.095

GERP RS

2.8

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.084

gMVP

0.20

Mutation Taster

=88/12

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over