20-63414925-G-C

Position:

chr20-63414925-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_172107.4(KCNQ2):c.1503C>G(p.Ala501=) 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:8

Conservation

PhyloP100: -4.28

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 129337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63414925-G-C is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.1503C>G	p.Ala501=	synonymous_variant	13/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7 linkuse as main transcript	c.1503C>G	p.Ala501=	synonymous_variant	13/17	1	NM_172107.4	A1	O43526-1

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

GnomAD3 exomes

AF:

0.0720

AC:

17856

AN:

248164

Hom.:

776

AF XY:

0.0720

AC XY:

9698

AN XY:

134642

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 SAS exome

AF:

0.0417

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

Gnomad4 AFR exome

AF:

0.146

Gnomad4 AMR exome

AF:

0.0546

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0439

Gnomad4 FIN exome

AF:

0.0699

Gnomad4 NFE exome

AF:

0.0815

Gnomad4 OTH exome

AF:

0.0801

GnomAD4 genome

AF:

0.0915

AC:

13905

AN:

151918

Hom.:

747

Cov.:

AF XY:

0.0901

AC XY:

6692

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.0779

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0372

Gnomad4 FIN

AF:

0.0679

Gnomad4 NFE

AF:

0.0804

Gnomad4 OTH

AF:

0.101

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2015

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. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Seizures, benign familial neonatal, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 26, 2017

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.014

DANN

Benign

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over