Genetic Variant KCNQ2:p.His228Gln (chr20-63444665-G-T) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_172107.4(KCNQ2):c.684C>A(p.His228Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H228R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 2.45

Publications

7 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: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_172107.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-63444667-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2857655.Status of the report is criteria_provided_single_submitter, 1 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 20-63444665-G-T is Pathogenic according to our data. Variant chr20-63444665-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 21797.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172107.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ2	NM_172107.4	MANE Select	c.684C>A	p.His228Gln	missense	Exon 4 of 17	NP_742105.1
KCNQ2	NM_001382235.1		c.684C>A	p.His228Gln	missense	Exon 4 of 17	NP_001369164.1
KCNQ2	NM_172106.3		c.684C>A	p.His228Gln	missense	Exon 4 of 16	NP_742104.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ2	ENST00000359125.7	TSL:1 MANE Select	c.684C>A	p.His228Gln	missense	Exon 4 of 17	ENSP00000352035.2
KCNQ2	ENST00000626839.2	TSL:1	c.684C>A	p.His228Gln	missense	Exon 4 of 16	ENSP00000486706.1
KCNQ2	ENST00000344462.8	TSL:1	c.684C>A	p.His228Gln	missense	Exon 4 of 16	ENSP00000339611.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1405038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691712

African (AFR)

AF:

0.00

AC:

AN:

32354

American (AMR)

AF:

0.00

AC:

AN:

38134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25084

East Asian (EAS)

AF:

0.00

AC:

AN:

37452

South Asian (SAS)

AF:

0.00

AC:

AN:

80528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5436

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079338

Other (OTH)

AF:

0.00

AC:

AN:

58010

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Pathogenic:1

Sep 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 228 of the KCNQ2 protein (p.His228Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with benign familial neonatal seizures (PMID: 4055306, 14534157; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21797). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function. For these reasons, this variant has been classified as Pathogenic.

Seizures, benign familial neonatal, 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

BFNE (benign familial neonatal epilepsy)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.18

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.1

PhyloP100

2.4

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.2

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.98

MutPred

0.91

Gain of methylation at K230 (P = 0.111)

MVP

1.0

MPC

2.8

ClinPred

1.0

GERP RS

0.71

PromoterAI

0.0097

Neutral

(source)

Varity_R

0.98

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over