chr20-63439613-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172107.4(KCNQ2):c.912C>T(p.Phe304Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0843 in 1,612,774 control chromosomes in the GnomAD database, including 9,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 1029 hom., cov: 33)

Exomes 𝑓: 0.085 ( 8770 hom. )

Consequence

KCNQ2
NM_172107.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.80

Publications

22 publications found

Variant links:

Genes affected

KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNQ2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
neonatal encephalopathy with non-epileptic myoclonus
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neonatal-onset developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
seizures, benign familial neonatal, 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
seizures, benign familial neonatal, 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
benign familial infantile epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
benign familial neonatal-infantile seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
benign neonatal seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNQ2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008976191).

BP6

Variant 20-63439613-G-A is Benign according to our data. Variant chr20-63439613-G-A is described in ClinVar as Benign. ClinVar VariationId is 129345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4 link	c.912C>T	p.Phe304Phe	synonymous_variant	Exon 6 of 17	ENST00000359125.7	NP_742105.1	O43526-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7 link	c.912C>T	p.Phe304Phe	synonymous_variant	Exon 6 of 17	1	NM_172107.4	ENSP00000352035.2		O43526-1

Frequencies

GnomAD3 genomes

AF:

0.0816

AC:

12427

AN:

152210

Hom.:

1030

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0170

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.0922

Gnomad EAS

AF:

0.454

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.0888

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0706

Gnomad OTH

AF:

0.0937

GnomAD2 exomes

AF:

0.120

AC:

30118

AN:

250874

AF XY:

0.119

show subpopulations

Gnomad AFR exome

AF:

0.0159

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.0957

Gnomad EAS exome

AF:

0.442

Gnomad FIN exome

AF:

0.0840

Gnomad NFE exome

AF:

0.0721

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.0845

AC:

123473

AN:

1460446

Hom.:

8770

Cov.:

AF XY:

0.0864

AC XY:

62811

AN XY:

726602

show subpopulations

African (AFR)

AF:

0.0145

AC:

486

AN:

33468

American (AMR)

AF:

0.168

AC:

7517

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0903

AC:

2359

AN:

26130

East Asian (EAS)

AF:

0.447

AC:

17731

AN:

39690

South Asian (SAS)

AF:

0.135

AC:

11655

AN:

86228

European-Finnish (FIN)

AF:

0.0834

AC:

4406

AN:

52850

Middle Eastern (MID)

AF:

0.113

AC:

653

AN:

5766

European-Non Finnish (NFE)

AF:

0.0655

AC:

72793

AN:

1111244

Other (OTH)

AF:

0.0973

AC:

5873

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

6033

12066

18100

24133

30166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2896

5792

8688

11584

14480

<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:

0.0815

AC:

12420

AN:

152328

Hom.:

1029

Cov.:

AF XY:

0.0881

AC XY:

6561

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0170

AC:

706

AN:

41586

American (AMR)

AF:

0.152

AC:

2322

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0922

AC:

320

AN:

3472

East Asian (EAS)

AF:

0.454

AC:

2344

AN:

5166

South Asian (SAS)

AF:

0.146

AC:

706

AN:

4830

European-Finnish (FIN)

AF:

0.0888

AC:

944

AN:

10626

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0706

AC:

4805

AN:

68018

Other (OTH)

AF:

0.0927

AC:

196

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

560

1119

1679

2238

2798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0756

Hom.:

1057

Bravo

AF:

0.0829

TwinsUK

AF:

0.0636

AC:

236

ALSPAC

AF:

0.0576

AC:

222

ESP6500AA

AF:

0.0213

AC:

ESP6500EA

AF:

0.0673

AC:

579

ExAC

AF:

0.114

AC:

13856

Asia WGS

AF:

0.256

AC:

887

AN:

3478

EpiCase

AF:

0.0782

EpiControl

AF:

0.0809

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 19. Only high quality variants are reported. -

not provided

Benign:3

Dec 06, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inborn genetic diseases

Benign:1

Dec 31, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.2

(source)

DANN

Benign

0.66

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0090

PhyloP100

4.8

Sift4G

Pathogenic

0.0

GERP RS

3.0

PromoterAI

-0.082

Neutral

(source)

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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