20-63438632-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_172107.4(KCNQ2):c.1016T>A(p.Leu339Gln) variant causes a missense 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. 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. L339R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.13

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 13 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, 2 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 chr20-63438632-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 21755.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, KCNQ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 20-63438632-A-T is Pathogenic according to our data. Variant chr20-63438632-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495272.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.1016T>A	p.Leu339Gln	missense_variant	7/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1016T>A	p.Leu339Gln	missense_variant	7/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

NeuroMeGen, Hospital Clinico Santiago de Compostela

Jan 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.96
MutPred		0.84		Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);.;Gain of disorder (P = 0.013);.;Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.99

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: rs118192217; hg19: chr20-62069985; COSMIC: COSV60433463; COSMIC: COSV60433463;