rs1057516089

chr20-63444700-T-Cchr20-63444700-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_172107.4(KCNQ2):c.649A>G(p.Thr217Ala) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T217N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 6.12

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 11 ACMG points.

• PM1: In a hotspot region, there are 12 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 chr20-63444699-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 813779.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, 0.936
• PP5: Variant 20-63444700-T-C is Pathogenic according to our data. Variant chr20-63444700-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 369757.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.649A>G	p.Thr217Ala	missense_variant	4/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.649A>G	p.Thr217Ala	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

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 13, 2022

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 217 of the KCNQ2 protein (p.Thr217Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with benign familial neonatal-infantile seizures (PMID: 23360469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 369757). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ2 function (PMID: 16319223). This variant disrupts the p.Thr217 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23621294). 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 Other:1

not provided, no classification provided

literature only

GeneReviews

-

BFIS (benign familial infantile seizures) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;L;.;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.;.
Vest4		0.93
MutPred		0.78		Gain of catalytic residue at T217 (P = 0.0435);Gain of catalytic residue at T217 (P = 0.0435);Gain of catalytic residue at T217 (P = 0.0435);Gain of catalytic residue at T217 (P = 0.0435);Gain of catalytic residue at T217 (P = 0.0435);.;Gain of catalytic residue at T217 (P = 0.0435);.;Gain of catalytic residue at T217 (P = 0.0435);Gain of catalytic residue at T217 (P = 0.0435);Gain of catalytic residue at T217 (P = 0.0435);.;
MVP		0.97
MPC		2.6
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.90
gMVP		0.96

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: rs1057516089; hg19: chr20-62076053;