rs1555850151

chr20-63406659-G-GGCCCA

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.2603_2604insTGGGC(p.Arg871GlyfsTer61) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A868A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 6.38

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 0.324 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-63406659-G-GGCCCA is Pathogenic according to our data. Variant chr20-63406659-G-GGCCCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 369815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.2603_2604insTGGGC	p.Arg871GlyfsTer61	frameshift_variant	17/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.2603_2604insTGGGC	p.Arg871GlyfsTer61	frameshift_variant	17/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

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

Apr 14, 2016

The c.2599_2603dupTGGGC variant, located in coding exon 17 of the KCNQ2 gene, results from a duplication of TGGGC at nucleotide positions 2599 to 2603. This duplication and subsequent frameshift occur near the 3' terminus of KCNQ2, is not expected to trigger nonsense mediated decay (NMD), and predicted to result in the elongation of the protein (p.R871Gfs*61). This alteration was first reported in a mother and daughter who had a diagnosis of benign familial neonatal epilepsy; while both had neonatal seizures, the daughter continued to have seizures outside of the neonatal period (Soldovieri MV et al. Hum Mutat. 2014; 35(3):356-67). Another study identified a different nucleotide change that results in the same protein change (referred to as 867ins) in a family with neonatal seizures; in vitro functional analysis indicated this alteration results in a dominant-negative affect and a >50% reduction in current magnitude (Singh NA et al. Brain. 2003; 126(Pt 12):2726-37). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), 1000 Genomes Project, and ExAC. In the ESP, this variant was not observed in 6196 samples (12392 alleles) with coverage at this position. In addition to the clinical and functional data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a variant is likely to be pathogenic (ACMG Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405-24). -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 05, 2022

This sequence change results in a frameshift in the KCNQ2 gene (p.Arg871Glyfs*61). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the KCNQ2 protein and extend the protein by 58 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 seizures (PMID: 14534157, 24375629). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 369815). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects KCNQ2 function (PMID: 14534157). For these reasons, this variant has been classified as Pathogenic. -

Seizures, benign familial neonatal, 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

BFNE (benign familial neonatal epilepsy) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555850151; hg19: chr20-62038012;