rs797044938

Positions:

• chr20-63442529-C-A
• chr20-63442529-C-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.693G>T​(p.Glu231Asp) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 29)
• Consequence: KCNQ2 NM_172107.4 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.33

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 15 ACMG points.

• PM1: In a helix (size 24) in uniprot entity KCNQ2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_172107.4
• 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, 0.92
• PP5: Variant 20-63442529-C-A is Pathogenic according to our data. Variant chr20-63442529-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211234.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.693G>T	p.Glu231Asp	missense_variant, splice_region_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.693G>T	p.Glu231Asp	missense_variant, splice_region_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

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2016

The p.E231D pathogenic mutation (also known as c.693G>T), located in coding exon 5 of the KCNQ2 gene, results from a G to T substitution at nucleotide position 693. The glutamic acid at codon 231 is replaced by aspartic acid, an amino acid with highly similar properties. A different nucleotide change (c.693G>C) which is located at the same position in KCNQ2 as the c.693G>T mutation and ultimately causes the amino acid change (p.E231D) was detected as a de novo event in a two year old male who presented as a newborn with epileptic encephalopathy, developmental delays, low tone and visual impairment (Helbig KL et al. Genet. Med., 2016 Sep;18:898-905). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Seizure Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 08, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;.;T;T;D;T;D;T;.;.;.;.
Eigen	Benign	0.098
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;M;.;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	.;.;.;.;D;.;D;N;D;D;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	.;.;.;.;D;.;D;T;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;.;D;D;D;D;T;D
Polyphen		0.37	B;.;.;.;.;.;B;.;B;P;.;.
Vest4		0.92
MutPred		0.69		Loss of ubiquitination at K230 (P = 0.0896);Loss of ubiquitination at K230 (P = 0.0896);Loss of ubiquitination at K230 (P = 0.0896);Loss of ubiquitination at K230 (P = 0.0896);Loss of ubiquitination at K230 (P = 0.0896);.;Loss of ubiquitination at K230 (P = 0.0896);.;Loss of ubiquitination at K230 (P = 0.0896);Loss of ubiquitination at K230 (P = 0.0896);Loss of ubiquitination at K230 (P = 0.0896);.;
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.89
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

LitVar

Other links and lift over

dbSNP: rs797044938; hg19: chr20-62073882;