chr20-63439609-CGAA-C

Variant names:

• chr20-63439609-CGAA-C
• rs118192212
• NM_172107.4:c.913_915delTTC

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.913_915delTTC​(p.Phe305del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:2
• Conservation: PhyloP100: 9.11

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 13 ACMG points.

• PM1: In a helix (size 41) in uniprot entity KCNQ2_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_172107.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 20-63439609-CGAA-C is Pathogenic according to our data. Variant chr20-63439609-CGAA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63439609-CGAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.913_915delTTC	p.Phe305del	conservative_inframe_deletion	Exon 6 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.913_915delTTC	p.Phe305del	conservative_inframe_deletion	Exon 6 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KCNQ2-related disorder Pathogenic:3

Dec 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ2 c.913_915delTTC (p.Phe305del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 250852 control chromosomes. c.913_915delTTC has been reported as de novo variant in the literature in individuals affected with KCNQ2-Related Disorders. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 35723786, 18640800). ClinVar contains an entry for this variant (Variation ID: 211236). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 14, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18640800) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:211236; PMID: 22884718; 32214227; 28728838; 27602407) - PS4. This variant is not present in population databases (rs118192212, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 32214227; 28728838) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. -

Jan 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNQ2 c.913_915delTTC variant is predicted to result in an in-frame deletion (p.Phe305del). This variant was reported in multiple individuals with KCNQ2-related conditions including benign familial neonatal epilepsy (Ishii et al 2009. PubMed ID: 18640800; reported as p.Phe304del), early infantile epileptic encephalopathy (Hengel et al 2020. PubMed ID: 32214227; Table S1 in Bayat et al 2022. PubMed ID: 35723786; Millichap et al 2016. PubMed ID: 27602407; Table S1 in Vanoye et al 2022. PubMed ID: 35104249), and intellectual disability and developmental delay (Supplementary data in Bowling et al 2017. PubMed ID: 28554332). This variant has interpretations of likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/211236/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Developmental and epileptic encephalopathy, 7 Pathogenic:3

Aug 01, 2019

Section for Clinical Neurogenetics, University of Tübingen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 16, 2021

Pediatrics, West China Second University Hospital, Sichuan University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:2

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect and significant impairment of potassium channel function (Ishii et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; Lost residue is predicted to be within the transmembrane segment S6; This variant is associated with the following publications: (PMID: 20437616, 18640800, 27602407, 28554332, 28728838, 32214227, 35401395) -

not specified Pathogenic:1

Dec 15, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo occurrence of the p.Phe305del variant has been reported in several individuals (Ishii 2009, Millichap 2016, Sterbova 2017, Bowling 2017, Spagnoli 2018) including identical twins (Millichap 2016). This variant is absent from general population databases including gnomAD but is listed in ClinVar with pathogenic classification (ClinVar ID 211236). The p.Phe305del variant is located in the Kv7.2 channel transmembrane segment 6, in the ion transport domain (IPR005821). Ishii et al. (2009) showed that this variant (reported as Phe304del) leads to null function with no current observed in the mutant KCNQ2 potassium channel. Based on the available evidence, this de novo p.Phe305del KCNQ2 gene variant was classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Jul 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe305 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25473036; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects KCNQ2 function (PMID: 18640800). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 211236). This variant is also known as c.910-2delTTC. This variant has been observed in individual(s) with KCNQ2-related conditions (PMID: 18640800, 27602407, 28728838). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.913_915del, results in the deletion of 1 amino acid(s) of the KCNQ2 protein (p.Phe305del), but otherwise preserves the integrity of the reading frame. -

Seizures, benign familial neonatal, 1 Pathogenic:1

Nov 10, 2021

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizure Pathogenic:1

Jun 26, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign Rolandic epilepsy Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

BECTS (benign childhood epilepsy with centrotemporal spikes) -

Complex neurodevelopmental disorder Other:1

-

Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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: rs118192212; hg19: chr20-62070962;