rs118192185

Positions:

• chr20-63472463-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.1A>G​(p.Met1?) variant causes a start lost 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: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 NM_172107.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.628

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 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-63472463-T-C is Pathogenic according to our data. Variant chr20-63472463-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21774.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.1A>G	p.Met1?	start_lost	1/17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1A>G	p.Met1?	start_lost	1/17	1	NM_172107.4	ENSP00000352035	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1355800 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 669354

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2024	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in patients with features consistent with KCNQ2-related epilepsy in published literature (PMID: 14985406, 25959266, 38814296); This variant is associated with the following publications: (PMID: 25982755, 27602407, 14985406, 19380078, 20437616, 25959266, 31440721, 38814296) -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change affects the initiator methionine of the KCNQ2 mRNA. The next in-frame methionine is located at codon 174. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with benign familial neonatal seizures (PMID: 14985406, 25982755). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21774). This variant disrupts the p.Arg144 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23934111, 25740509). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Seizures, benign familial neonatal, 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

BFNE (benign familial neonatal epilepsy) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;.;T;T;T;T;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PROVEAN	Benign	-1.6	.;.;.;.;N;N;N;N;N
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	.;.;.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.92	P;.;.;.;.;P;P;P;.
Vest4		0.67
MutPred		1.0		Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);
MVP		0.98
ClinPred		0.95	D
GERP RS		2.1
Varity_R		0.90
gMVP		0.83

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: rs118192185; hg19: chr20-62103816;