NM_004519.4:c.1071C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004519.4(KCNQ3):c.1071C>G(p.Leu357Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,613,580 control chromosomes in the GnomAD database, including 3,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L357L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.051 ( 315 hom., cov: 33)

Exomes 𝑓: 0.064 ( 3356 hom. )

Consequence

KCNQ3
NM_004519.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.194

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 8-132172667-G-C is Benign according to our data. Variant chr8-132172667-G-C is described in ClinVar as Benign. ClinVar VariationId is 129347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.194 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

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.1071C>G	p.Leu357Leu	synonymous	Exon 7 of 15	NP_004510.1	O43525-1
	KCNQ3	NM_001204824.2		c.711C>G	p.Leu237Leu	synonymous	Exon 7 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.1071C>G	p.Leu357Leu	synonymous	Exon 7 of 15	ENSP00000373648.3	O43525-1
KCNQ3	ENST00000519445.5	TSL:5	c.1071C>G	p.Leu357Leu	synonymous	Exon 7 of 15	ENSP00000428790.1	E7ET42
KCNQ3	ENST00000521134.6	TSL:2	c.711C>G	p.Leu237Leu	synonymous	Exon 7 of 15	ENSP00000429799.1	O43525-2

Frequencies

GnomAD3 genomes

AF:

0.0512

AC:

7784

AN:

152180

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0738

Gnomad OTH

AF:

0.0455

GnomAD2 exomes

AF:

0.0523

AC:

13119

AN:

250804

AF XY:

0.0529

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.0233

Gnomad ASJ exome

AF:

0.0413

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.124

Gnomad NFE exome

AF:

0.0729

Gnomad OTH exome

AF:

0.0534

GnomAD4 exome

AF:

0.0645

AC:

94228

AN:

1461282

Hom.:

3356

Cov.:

AF XY:

0.0632

AC XY:

45961

AN XY:

726970

show subpopulations

African (AFR)

AF:

0.0125

AC:

420

AN:

33476

American (AMR)

AF:

0.0245

AC:

1097

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0398

AC:

1041

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0163

AC:

1403

AN:

86254

European-Finnish (FIN)

AF:

0.121

AC:

6417

AN:

53096

Middle Eastern (MID)

AF:

0.0482

AC:

278

AN:

5768

European-Non Finnish (NFE)

AF:

0.0721

AC:

80123

AN:

1111748

Other (OTH)

AF:

0.0571

AC:

3446

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

4560

9120

13680

18240

22800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2830

5660

8490

11320

14150

<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:

0.0511

AC:

7781

AN:

152298

Hom.:

315

Cov.:

AF XY:

0.0517

AC XY:

3849

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0152

AC:

632

AN:

41560

American (AMR)

AF:

0.0297

AC:

454

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

124

AN:

3470

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.0128

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.124

AC:

1316

AN:

10616

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0738

AC:

5023

AN:

68028

Other (OTH)

AF:

0.0450

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

388

776

1164

1552

1940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0507

Hom.:

Bravo

AF:

0.0435

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0673

EpiControl

AF:

0.0660

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Benign neonatal seizures (2)

not provided (2)

Inborn genetic diseases (1)

not specified (1)

Seizures, benign familial neonatal, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.9

(source)

DANN

Benign

0.80

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism (auto)

(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