rs1057516101

Positions:

• chr20-63439599-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.926C>T​(p.Ala309Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense, splice_region
• Scores: Splicing: ADA: 0.6486
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.77

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 15 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, 3 uncertain in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNQ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 20-63439599-G-A is Pathogenic according to our data. Variant chr20-63439599-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 369772.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.926C>T	p.Ala309Val	missense_variant, splice_region_variant	6/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.926C>T	p.Ala309Val	missense_variant, splice_region_variant	6/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Aug 10, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 10, 2020

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with KCNQ2-related conditions (PMID: 23692823, 29314763, 30776697). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 369772). This sequence change replaces alanine with valine at codon 309 of the KCNQ2 protein (p.Ala309Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;.;.;.;.;.;L;.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.90
MutPred		0.66		Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);.;Loss of glycosylation at S314 (P = 0.3536);.;Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);
MVP		0.99
MPC		2.8
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.65
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.080		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: rs1057516101; hg19: chr20-62070952;