chr20-63406640-C-T

Position:

chr20-63406640-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172107.4(KCNQ2):c.*4G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,587,226 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 5 hom. )

Consequence

KCNQ2
NM_172107.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.27

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 20-63406640-C-T is Benign according to our data. Variant chr20-63406640-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 167205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63406640-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00203 (309/152260) while in subpopulation NFE AF= 0.00348 (237/68012). AF 95% confidence interval is 0.00312. There are 0 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.*4G>A		3_prime_UTR_variant	17/17	ENST00000359125.7	NP_742105.1	O43526-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125 linkuse as main transcript	c.*4G>A		3_prime_UTR_variant	17/17	1	NM_172107.4	ENSP00000352035.2		O43526-1

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00348

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00225

AC:

466

AN:

207336

Hom.:

AF XY:

0.00230

AC XY:

265

AN XY:

115052

show subpopulations

Gnomad AFR exome

AF:

0.000335

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000221

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00112

Gnomad FIN exome

AF:

0.000708

Gnomad NFE exome

AF:

0.00395

Gnomad OTH exome

AF:

0.00269

GnomAD4 exome

AF:

0.00264

AC:

3791

AN:

1434966

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

1812

AN XY:

712462

show subpopulations

Gnomad4 AFR exome

AF:

0.000332

Gnomad4 AMR exome

AF:

0.00144

Gnomad4 ASJ exome

AF:

0.000156

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000993

Gnomad4 FIN exome

AF:

0.00120

Gnomad4 NFE exome

AF:

0.00312

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.00203

AC:

309

AN:

152260

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00348

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00219

Hom.:

Bravo

AF:

0.00222

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2016

This alteration is classified as likely 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. -

KCNQ2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

KCNQ2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.45

DANN

Benign

0.85

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

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