NM_004519.4:c.1564G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_004519.4(KCNQ3):c.1564G>A(p.Val522Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,591,502 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V522D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

KCNQ3
NM_004519.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 3.92

Publications

3 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):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
seizures, benign familial neonatal, 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
self-limited familial neonatal epilepsy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
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, ClinGen

KCNQ3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21538198).

BP6

Variant 8-132140080-C-T is Benign according to our data. Variant chr8-132140080-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193878.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ3	NM_004519.4	MANE Select	c.1564G>A	p.Val522Ile	missense	Exon 11 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.1204G>A	p.Val402Ile	missense	Exon 11 of 15	NP_001191753.1	O43525-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ3	ENST00000388996.10	TSL:1 MANE Select	c.1564G>A	p.Val522Ile	missense	Exon 11 of 15	ENSP00000373648.3	O43525-1
KCNQ3	ENST00000519445.5	TSL:5	c.1564G>A	p.Val522Ile	missense	Exon 11 of 15	ENSP00000428790.1	E7ET42
KCNQ3	ENST00000521134.6	TSL:2	c.1204G>A	p.Val402Ile	missense	Exon 11 of 15	ENSP00000429799.1	O43525-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000789

AC:

AN:

228138

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.0000627

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1439314

Hom.:

Cov.:

AF XY:

0.0000392

AC XY:

AN XY:

713940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33158

American (AMR)

AF:

0.0000464

AC:

AN:

43074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24224

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39498

South Asian (SAS)

AF:

0.0000613

AC:

AN:

81572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51714

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.0000527

AC:

AN:

1100922

Other (OTH)

AF:

0.0000168

AC:

AN:

59506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.0000460

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41526

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.0000434

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Benign neonatal seizures (2)

not provided (2)

Inborn genetic diseases (1)

Seizures, benign familial neonatal, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.053

MetaRNN

Benign

0.22

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.3

PhyloP100

3.9

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.24

REVEL

Uncertain

0.41

Sift

Benign

0.72

Sift4G

Benign

1.0

Polyphen

0.91

Vest4

0.35

MVP

0.90

MPC

1.4

ClinPred

0.13

GERP RS

6.0

Varity_R

0.21

gMVP

0.40

Mutation Taster

=76/24

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

Computational scores

Splicing

Publications

Other links and lift over