rs773171451

chr20-63413535-G-Achr20-63413535-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_172107.4(KCNQ2):c.1678C>T(p.Arg560Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R560Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:2
• Conservation: PhyloP100: 2.64

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 17 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_172107.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63413534-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, KCNQ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 20-63413535-G-A is Pathogenic according to our data. Variant chr20-63413535-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205915.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.1678C>T	p.Arg560Trp	missense_variant	15/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1678C>T	p.Arg560Trp	missense_variant	15/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461084 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 7 Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 26, 2021	_x000D_ Criteria applied: PS2, PS3_MOD, PS4_MOD, PM1, PM5, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Nov 05, 2020	0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with early infantile epileptic encephalopathy, 7 (EIEE) (MIM#613720) and benign neonatal seizures, 1 (BNS) (MIM# 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however, this is only reported for patients with BNS (PMID 25959266). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated KCNQ voltage-gated potassium channel (NCBI, PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change (p.Arg560Gln) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and has been observed in several de novo patients with EIEE (Decipher, ClinVar, PMID: 22275249, PMID: 25880994). (SP) 1207 - Parental origin of the variant is unresolved. This variant was not maternally inherited (20G001811). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2022	Functional studies show that R560W (reported as R532W using alternative nomenclature) alters the expression and function of the Kv7.2 and Kv7.3 potassium channels (Orhan et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 31152295, 24318194, 22275249, 27652284, 28488083, 25880994, 31832524, 32139178, 32573669, 32581362, 33192566, 30008368, 32917465, 33726816, 31175295, 27602407) -

Global developmental delay;C0751093:Limb dystonia;C1854882:Absent speech Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2022

The c.1678C>T (p.R560W) alteration is located in exon 15 (coding exon 15) of the KCNQ2 gene. This alteration results from a C to T substitution at nucleotide position 1678, causing the arginine (R) at amino acid position 560 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in multiple individuals with neonatal epileptic encephalopathy (Kim, 2021; Na, 2020, Ma, 2019, Australian Genomics Health Alliance Acute Care Flagship, 2020) and has been found to be de novo in several unrelated affected individuals (Xu, 2021; Weckhuysen, 2012; Pisano, 2015; Oates, 2018; Fang, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 22, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 560 of the KCNQ2 protein (p.Arg560Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-infantile epileptic encephalopathy (PMID: 22275249, 25880994). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205915). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 24318194). For these reasons, this variant has been classified as Pathogenic. -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Feb 24, 2021

- -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.96
MutPred		0.71		.;.;.;.;.;.;Loss of disorder (P = 0.0201);.;.;.;.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.95
gMVP		0.97

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: rs773171451; hg19: chr20-62044888;