chr20-63406886-C-T

Position:

chr20-63406886-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The ENST00000359125.7(KCNQ2):c.2377G>A(p.Val793Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,459,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V793L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

KCNQ2
ENST00000359125.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.68

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 Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ2. . Gene score misZ 4.0411 (greater than the threshold 3.09). Trascript score misZ 3.6968 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.2377G>A	p.Val793Met	missense_variant	17/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7 linkuse as main transcript	c.2377G>A	p.Val793Met	missense_variant	17/17	1	NM_172107.4	ENSP00000352035	A1	O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

245912

Hom.:

AF XY:

0.0000299

AC XY:

AN XY:

133784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000452

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000891

AC:

AN:

1459480

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725954

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000579

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 793 of the KCNQ2 protein (p.Val793Met). This variant is present in population databases (rs377227909, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of developmental and epileptic encephalopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 1025174). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 11, 2020

This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

.;T;T;T;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.43

T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.9

.;.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.1

.;.;N;.;N;.

REVEL

Benign

0.18

Sift

Pathogenic

0.0

.;.;D;.;D;.

Sift4G

Uncertain

0.0050

D;.;D;D;D;D

Polyphen

0.96

D;.;D;.;D;D

Vest4

0.50

MutPred

0.39

.;.;Loss of sheet (P = 0.1907);.;.;.;

MVP

0.80

MPC

1.4

ClinPred

0.66

GERP RS

5.0

Varity_R

0.27

gMVP

0.72

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