chr20-63433897-A-G

Variant names:

• chr20-63433897-A-G
• rs1057516105
• NM_172107.4:c.1030T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_172107.4(KCNQ2):​c.1030T>C​(p.Trp344Arg) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.52

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 Likely_pathogenic. Variant got 9 ACMG points.

• 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, 0.955
• PP5: Variant 20-63433897-A-G is Pathogenic according to our data. Variant chr20-63433897-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 369777.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-63433897-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.1030T>C	p.Trp344Arg	missense_variant	Exon 8 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1030T>C	p.Trp344Arg	missense_variant	Exon 8 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Mar 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 24375629, 26073431, 34020651). 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. ClinVar contains an entry for this variant (Variation ID: 369777). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 24375629). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 344 of the KCNQ2 protein (p.Trp344Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Seizures, benign familial neonatal, 1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

BFNE (benign familial neonatal epilepsy) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;T;T;T;T;D;T;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.;.;.;.;.;M;.;M;M;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-13	.;.;.;.;D;.;D;.;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;.
Vest4		1.0
MutPred		0.72		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);.;Gain of loop (P = 0.0435);.;Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);
MVP		0.99
MPC		4.3
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
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: rs1057516105; hg19: chr20-62065250;