rs1555871832

Positions:

• chr20-63442444-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The ENST00000359125.7(KCNQ2):​c.778C>T​(p.His260Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: KCNQ2 ENST00000359125.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.70

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000359125.7
• 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.
• PP5: Variant 20-63442444-G-A is Pathogenic according to our data. Variant chr20-63442444-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.778C>T	p.His260Tyr	missense_variant	5/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.778C>T	p.His260Tyr	missense_variant	5/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 495248). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 31780880). In at least one individual the variant was observed to be de novo. This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 260 of the KCNQ2 protein (p.His260Tyr). -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

NeuroMeGen, Hospital Clinico Santiago de Compostela

Jan 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;.;T;T;D;T;D;T;.;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.6	L;.;.;.;.;.;L;.;L;L;L;.
MutationTaster	Benign	0.65	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.6	.;.;.;.;D;.;D;.;D;D;D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	.;.;.;.;D;.;D;.;D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		0.24	B;.;.;.;.;.;B;.;B;B;.;.
Vest4		0.56
MutPred		0.37		Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);.;Loss of disorder (P = 0.0429);.;Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);.;
MVP		0.73
MPC		2.1
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.49
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1555871832; hg19: chr20-62073797;