rs118192244

Positions:

• chr20-63407135-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.2127del​(p.Val710SerfsTer220) variant causes a frameshift 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: -1.06

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.188 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-63407135-CA-C is Pathogenic according to our data. Variant chr20-63407135-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 7390.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.2127del	p.Val710SerfsTer220	frameshift_variant	17/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.2127del	p.Val710SerfsTer220	frameshift_variant	17/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial neonatal, 1 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	-	- -
not provided, no classification provided	literature only	GeneReviews	-	BFNE (benign familial neonatal epilepsy) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 12, 2006	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2023

Experimental studies have shown that this frameshift affects KCNQ2 function (PMID: 2847176, 16260777). This sequence change results in a frameshift in the KCNQ2 gene (p.Val710Serfs*220). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 163 amino acid(s) of the KCNQ2 protein and extend the protein by 56 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with benign familial neonatal convulsions (PMID: 12847176, 16966552, 27535030). This variant is also known as c.2043del. ClinVar contains an entry for this variant (Variation ID: 7390). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant disrupts a region of the KCNQ2 protein in which other variant(s) (p.Cys774Leufs*91) have been determined to be pathogenic (PMID: 23692823). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 22, 2014

c.2127delT: p.Val710SerfsX220 (V710SfsX220) in exon 17 of the KCNQ2 gene (NM_172107.2). The normal sequence with the base that is deleted in braces is: GCCCCC{T}GTCC.The c.2127delT mutation in the KCNQ2 gene has been reported previously in association with benign familial neonatal seizures (Coppola et al., 2003). The deletion causes a frameshift starting with codon Valine 710, changes this amino acid to a Serine residue and creates a premature Stop codon at position 220 of the new reading frame, denoted p.Val710SerfsX220. This results in the replacement of the last 163 amino acids of the KCNQ2 protein with 219 incorrect amino acids. The variant is found in INFANT-EPI panel(s). -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Nov 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs118192244; hg19: chr20-62038488;