20-63444779-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_172107.4(KCNQ2):c.570C>A(p.Asn190Lys) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N190I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.436

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr20-63444780-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3068827.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, KCNQ2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.570C>A	p.Asn190Lys	missense_variant	4/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.570C>A	p.Asn190Lys	missense_variant	4/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 23, 2020

This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 190 of the KCNQ2 protein (p.Asn190Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant has not been reported in the literature in individuals with KCNQ2-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;M;.;M;M;M
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.0090	D;D;D;D;D;.;D;D;D;D;D
Polyphen		0.96	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.93
MutPred		0.63		Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);.;Gain of MoRF binding (P = 0.0316);.;Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);
MVP		0.88
MPC		2.8
ClinPred		1.0	D
GERP RS		-4.1
Varity_R		0.85
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-62076132;