chr20-63438654-T-C

Position:

• chr20-63438654-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.994A>G​(p.Arg332Gly) variant causes a missense change involving the alteration of a non-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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.935

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ2. . Gene score misZ 4.0411 (greater than the threshold 3.09). Trascript score misZ 3.6968 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.848
• PP5: Variant 20-63438654-T-C is Pathogenic according to our data. Variant chr20-63438654-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 461424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.994A>G	p.Arg332Gly	missense_variant	7/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.994A>G	p.Arg332Gly	missense_variant	7/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2016

The p.R332G variant (also known as c.994A>G), located in coding exon 7 of the KCNQ2 gene, results from an A to G substitution at nucleotide position 994. The arginine at codon 332 is replaced by glycine, an amino acid with dissimilar properties. This variant has been determined to be the result of a de novo mutation in one individual with neonatal epileptic encephalopathy in our laboratory. However, the possibility of mosaicism, including in the germline of this individual's parent, could not be ruled out. This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), 1000 Genomes Project, ExAC, and gnomAD. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 11, 2017

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Family studies have indicated that this variant was not present in the parents of an individual with generalized epilepsy , which suggests that it was de novo in that affected individual (Invitae). This sequence change replaces arginine with glycine at codon 332 of the KCNQ2 protein (p.Arg332Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. In summary, this variant is a novel missense change that has been shown to arise de novo in an affected individual. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNQ2-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;.;T;T;T;T;D;T;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.73	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.85	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	0.92	D
PROVEAN	Pathogenic	-6.4	.;.;.;.;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		0.97	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.88
MutPred		0.56		Gain of ubiquitination at K331 (P = 0.0301);Gain of ubiquitination at K331 (P = 0.0301);Gain of ubiquitination at K331 (P = 0.0301);Gain of ubiquitination at K331 (P = 0.0301);Gain of ubiquitination at K331 (P = 0.0301);.;Gain of ubiquitination at K331 (P = 0.0301);.;Gain of ubiquitination at K331 (P = 0.0301);Gain of ubiquitination at K331 (P = 0.0301);Gain of ubiquitination at K331 (P = 0.0301);
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		1.5
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555869758; hg19: chr20-62070007;