20-63442518-G-A

Position:

• chr20-63442518-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The ENST00000359125.7(KCNQ2):​c.704C>T​(p.Ala235Val) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A235T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: KCNQ2 ENST00000359125.7 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.77

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 16 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000359125.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63442518-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1959325.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.804
• PP5: Variant 20-63442518-G-A is Pathogenic according to our data. Variant chr20-63442518-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211235.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.704C>T	p.Ala235Val	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.704C>T	p.Ala235Val	missense_variant	5/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2018

The p.A235V variant (also known as c.704C>T), located in coding exon 5 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 704. The alanine at codon 235 is replaced by valine, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in two unrelated families with an isolated case of KCNQ2-related epileptic encephalopathy (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;.;T;T;D;T;D;T;.;.;.;.
Eigen	Benign	-0.015
Eigen_PC	Benign	0.082
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.3	L;.;.;.;.;.;L;.;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	.;.;.;.;D;.;D;.;D;D;D;.
REVEL	Pathogenic	0.75
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		0.0040	B;.;.;.;.;.;B;.;B;B;.;.
Vest4		0.91
MutPred		0.62		Gain of ubiquitination at K230 (P = 0.1278);Gain of ubiquitination at K230 (P = 0.1278);Gain of ubiquitination at K230 (P = 0.1278);Gain of ubiquitination at K230 (P = 0.1278);Gain of ubiquitination at K230 (P = 0.1278);.;Gain of ubiquitination at K230 (P = 0.1278);.;Gain of ubiquitination at K230 (P = 0.1278);Gain of ubiquitination at K230 (P = 0.1278);Gain of ubiquitination at K230 (P = 0.1278);.;
MVP		1.0
MPC		1.6
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.73
gMVP		0.98

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: rs797045638; hg19: chr20-62073871;