rs1057516101

Variant names:

• chr20-63439599-G-A
• rs1057516101
• NM_172107.4:c.926C>T

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 helix (size 41) in uniprot entity KCNQ2_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.
• 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 rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.926C>T	p.Ala309Val	missense_variant, splice_region_variant	Exon 6 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.926C>T	p.Ala309Val	missense_variant, splice_region_variant	Exon 6 of 17	1	NM_172107.4	ENSP00000352035.2

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

Aug 10, 2017

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

EE (epileptic encephalopathy) -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Mar 10, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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. 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). 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. For these reasons, this variant has been classified as Pathogenic. -

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
DEOGEN2	Uncertain	0.45	.;.;T;T;D;T;D;T;.;.;.
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
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	.;.;.;.;D;.;D;.;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;D;D;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;