rs886041262

chr20-63444720-C-Gchr20-63444720-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_172107.4(KCNQ2):c.629G>C(p.Arg210Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R210C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.90

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 14 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 chr20-63444721-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205873.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, 0.93
• PP5: Variant 20-63444720-C-G is Pathogenic according to our data. Variant chr20-63444720-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63444720-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.629G>C	p.Arg210Pro	missense_variant	4/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.629G>C	p.Arg210Pro	missense_variant	4/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2016	The R210P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, different missense variants at the same position (R210C, R210H) have been reported previously in association with KCNQ2-related disorders (Stenson et al., 2014). The R210P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R210P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within the voltage-sensor transmembrane segment S4 of the protein, and multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the R210P variant is considered to be a pathogenic variant -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg210 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24107868, 24371303, 25880994, 26446091, 28283543). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 280614). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 210 of the KCNQ2 protein (p.Arg210Pro). -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Mar 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;.;H;.;H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		0.92	P;.;.;.;.;.;P;.;P;P;.;.
Vest4		0.94
MutPred		0.67		Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);.;Loss of MoRF binding (P = 0.0075);.;Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);.;
MVP		0.99
MPC		3.4
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.99
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: rs886041262; hg19: chr20-62076073;