rs118192200

Positions:

• chr20-63444729-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.620G>A​(p.Arg207Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 7.74

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 19 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63444730-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7386.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, 0.99
• PP5: Variant 20-63444729-C-T is Pathogenic according to our data. Variant chr20-63444729-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63444729-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.620G>A	p.Arg207Gln	missense_variant	4/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.620G>A	p.Arg207Gln	missense_variant	4/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451256 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720834

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2022	Previously reported in an individual with myokymia due to peripheral nerve hyperexcitability, and functional studies indicate this variant alters voltage-dependent activation (Wuttke et al., 2007; Miceli et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17872363, 29655203, 22455920, 32184343, 25959266, 25741868, 24375629, 22169383, 11572947, 32884139, 32506321, 33098118) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 08, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/270462 chr). Predicted to have a damaging effect on the protein. One de novo case with parental identity confirmed. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2023

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the KCNQ2 protein (p.Arg207Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 17872363, 25959266, 29655203, 32184343, 34711204). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7391). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 17872363, 22455920). This variant disrupts the p.Arg207 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11572947, 22169383, 22455920, 24375629). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Seizures, benign familial neonatal, 1, and/or myokymia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 27, 2007

- -

Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Developmental and epileptic encephalopathy, 7 Other:1

not provided, no classification provided

literature only

GeneReviews

-

Myokymia, EE (epileptic encephalopathy) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.;M;.;M;M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.058	T;T;D;D;D;.;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.;.
Vest4		0.99
MutPred		0.97		Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);.;Loss of MoRF binding (P = 0.0655);.;Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);Loss of MoRF binding (P = 0.0655);.;
MVP		1.0
MPC		3.0
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		1.0

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: rs118192200; hg19: chr20-62076082; COSMIC: COSV60431547; COSMIC: COSV60431547;