Genetic Variant NM_172107.4:c.1503C>G (chr20-63414925-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The NM_172107.4(KCNQ2):c.1503C>G(p.Ala501Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0792 in 1,612,436 control chromosomes in the GnomAD database, including 5,593 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. A501A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.092 ( 747 hom., cov: 32)

Exomes 𝑓: 0.078 ( 4846 hom. )

Consequence

KCNQ2
NM_172107.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -4.28

Publications

10 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 20-63414925-G-C is Benign according to our data. Variant chr20-63414925-G-C is described in ClinVar as Benign. ClinVar VariationId is 129337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.28 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172107.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ2	NM_172107.4	MANE Select	c.1503C>G	p.Ala501Ala	synonymous	Exon 13 of 17	NP_742105.1
KCNQ2	NM_001382235.1		c.1449C>G	p.Ala483Ala	synonymous	Exon 12 of 17	NP_001369164.1
KCNQ2	NM_172106.3		c.1449C>G	p.Ala483Ala	synonymous	Exon 12 of 16	NP_742104.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.1503C>G	p.Ala501Ala	synonymous	Exon 13 of 17	ENSP00000352035.2
KCNQ2	ENST00000626839.2	TSL:1	c.1449C>G	p.Ala483Ala	synonymous	Exon 12 of 16	ENSP00000486706.1
KCNQ2	ENST00000344462.8	TSL:1	c.1413C>G	p.Ala471Ala	synonymous	Exon 12 of 16	ENSP00000339611.4

Frequencies

GnomAD3 genomes

AF:

0.0916

AC:

13907

AN:

151800

Hom.:

749

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0780

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0376

Gnomad FIN

AF:

0.0679

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.0803

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.0720

AC:

17856

AN:

248164

AF XY:

0.0720

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.0506

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0697

Gnomad NFE exome

AF:

0.0853

Gnomad OTH exome

AF:

0.0863

GnomAD4 exome

AF:

0.0779

AC:

113733

AN:

1460518

Hom.:

4846

Cov.:

AF XY:

0.0771

AC XY:

56023

AN XY:

726608

show subpopulations

African (AFR)

AF:

0.146

AC:

4884

AN:

33474

American (AMR)

AF:

0.0546

AC:

2444

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2809

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.0439

AC:

3790

AN:

86246

European-Finnish (FIN)

AF:

0.0699

AC:

3654

AN:

52270

Middle Eastern (MID)

AF:

0.123

AC:

704

AN:

5702

European-Non Finnish (NFE)

AF:

0.0815

AC:

90608

AN:

1111910

Other (OTH)

AF:

0.0801

AC:

4834

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

5479

10958

16436

21915

27394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3316

6632

9948

13264

16580

<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:

0.0915

AC:

13905

AN:

151918

Hom.:

747

Cov.:

AF XY:

0.0901

AC XY:

6692

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.137

AC:

5660

AN:

41414

American (AMR)

AF:

0.0779

AC:

1191

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

385

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.0372

AC:

178

AN:

4788

European-Finnish (FIN)

AF:

0.0679

AC:

719

AN:

10596

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0804

AC:

5461

AN:

67950

Other (OTH)

AF:

0.101

AC:

212

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

654

1308

1961

2615

3269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0634

Hom.:

126

Bravo

AF:

0.0964

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0889

EpiControl

AF:

0.0920

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Seizures, benign familial neonatal, 1

Benign:1

Apr 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.014

(source)

DANN

Benign

0.43

PhyloP100

-4.3

PromoterAI

-0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over