rs796052650

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_172107.4(KCNQ2):c.1639C>T(p.Arg547Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 0.0970

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

PP5

Variant 20-63413574-G-A is Pathogenic according to our data. Variant chr20-63413574-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63413574-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4 linkuse as main transcript	c.1639C>T	p.Arg547Trp	missense_variant	15/17	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.1639C>T	p.Arg547Trp	missense_variant	15/17	1	NM_172107.4	ENSP00000352035	A1	O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459140

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2022	Identified in unrelated patients with clinical features consistent with a KCNQ2-related disorder referred for genetic testing at GeneDx and in patients with neonatal-onset seizures in the published literature (Zara et al., 2013; Panjan et al., 2021; Amore et al., 2022); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28717674, 29655203, 34474328, 35401395, 29455050, 23360469, 27602407) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 02, 2016	- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 547 of the KCNQ2 protein (p.Arg547Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with benign familial neonatal-infantile seizures (PMID: 23360469, 29655203; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 205912). 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. For these reasons, this variant has been classified as Pathogenic. -

Seizures, benign familial neonatal, 1

Other:1

not provided, no classification provided

literature only

GeneReviews

BFNE (benign familial neonatal epilepsy) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;.;T;T;D;T;D;T;.;.;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.89

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

.;.;.;.;.;.;M;.;.;.;.

MutationTaster

Benign

0.96

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

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.2

.;.;.;.;D;.;D;.;D;.;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

.;.;.;.;D;.;D;.;D;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;.;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;D;.;D;D;.

Vest4

0.85

MutPred

0.69

.;.;.;.;.;.;Loss of MoRF binding (P = 0.0876);.;.;.;.;

MVP

0.97

MPC

1.6

ClinPred

1.0

GERP RS

-1.1

Varity_R

0.89

gMVP

0.96

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