rs748400155

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBP6BS2

The NM_172107.4(KCNQ2):c.2329C>T(p.Pro777Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000238 in 1,598,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P777R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.47

Publications

1 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: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_172107.4

PP2

Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to benign familial infantile epilepsy, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, 7, benign familial neonatal-infantile seizures, benign neonatal seizures, neonatal-onset developmental and epileptic encephalopathy, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, seizures, benign familial neonatal, 1, neonatal encephalopathy with non-epileptic myoclonus.

BP4

Computational evidence support a benign effect (MetaRNN=0.08846113).

BP6

Variant 20-63406934-G-A is Benign according to our data. Variant chr20-63406934-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205850.

BS2

High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4 link	c.2329C>T	p.Pro777Ser	missense_variant	Exon 17 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.2329C>T	p.Pro777Ser	missense_variant	Exon 17 of 17	1	NM_172107.4	ENSP00000352035.2		O43526-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000138

AC:

AN:

217700

AF XY:

0.0000250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000207

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000256

AC:

AN:

1446590

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

718944

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33336

American (AMR)

AF:

0.00

AC:

AN:

43574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39200

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46628

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000280

AC:

AN:

1107450

Other (OTH)

AF:

0.0000501

AC:

AN:

59850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000500

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNQ2: PP2, BP4, BP5 -

May 04, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy

Uncertain:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 777 of the KCNQ2 protein (p.Pro777Ser). This variant is present in population databases (rs748400155, gnomAD 0.003%). This missense change has been observed in individuals with KCNQ2 related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 205850). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Continuous spike and waves during slow sleep

Uncertain:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 25, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Intellectual disability

Benign:1

May 16, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.25

CADD

Benign

8.3

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.012

.;T;T;T;.;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.75

T;T;T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.088

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;.;L;.;.;.

PhyloP100

3.5

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.86

.;.;N;N;N;.

REVEL

Benign

0.079

Sift

Benign

0.16

.;.;T;T;T;.

Sift4G

Benign

0.73

T;.;T;T;T;T

Polyphen

0.0

B;.;B;.;B;B

Vest4

0.028

MutPred

0.17

.;.;Loss of catalytic residue at P776 (P = 0.0131);.;.;.;

MVP

0.48

MPC

0.63

ClinPred

0.027

GERP RS

1.9

Varity_R

0.025

gMVP

0.16

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over