rs150821246

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_004519.4(KCNQ3):c.2263G>A(p.Asp755Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000486 in 1,614,058 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 1 hom. )

Consequence

KCNQ3
NM_004519.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11O:1

Conservation

PhyloP100: 4.36

Publications

9 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060245782).

BP6

Variant 8-132129618-C-T is Benign according to our data. Variant chr8-132129618-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 205988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000296 (45/152208) while in subpopulation NFE AF = 0.000515 (35/68006). AF 95% confidence interval is 0.00038. There are 1 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2263G>A	p.Asp755Asn	missense	Exon 15 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.1903G>A	p.Asp635Asn	missense	Exon 15 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.2263G>A	p.Asp755Asn	missense	Exon 15 of 15	ENSP00000373648.3	O43525-1
KCNQ3	ENST00000519445.5	TSL:5	c.2227G>A	p.Asp743Asn	missense	Exon 15 of 15	ENSP00000428790.1	E7ET42
KCNQ3	ENST00000521134.6	TSL:2	c.1903G>A	p.Asp635Asn	missense	Exon 15 of 15	ENSP00000429799.1	O43525-2

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000515

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000374

AC:

AN:

251012

AF XY:

0.000376

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000731

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000506

AC:

739

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

362

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000630

AC:

701

AN:

1111996

Other (OTH)

AF:

0.000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000296

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41534

American (AMR)

AF:

0.000458

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000609

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000404

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000949

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Benign neonatal seizures (2)

Inborn genetic diseases (1)

KCNQ3-related disorder (1)

Seizures, benign familial neonatal, 2 (2)

Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.060

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.1

PhyloP100

4.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.88

REVEL

Uncertain

0.40

Sift

Benign

0.16

Sift4G

Benign

0.34

Polyphen

1.0

Vest4

0.36

MVP

0.81

MPC

0.44

ClinPred

0.14

GERP RS

5.3

Varity_R

0.14

gMVP

0.51

Mutation Taster

=97/3

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

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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