rs118192226

Positions:

• chr20-63415086-G-A
• chr20-63415086-G-T

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.1342C>T​(p.Arg448Ter) variant causes a stop gained change. 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R448R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 NM_172107.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 3.72

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-63415086-G-A is Pathogenic according to our data. Variant chr20-63415086-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63415086-G-A is described in Lovd as [Pathogenic]. Variant chr20-63415086-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.1342C>T	p.Arg448Ter	stop_gained	13/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.1342C>T	p.Arg448Ter	stop_gained	13/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451988 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 722816

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11690625, 25525159, 16686649, 18698150, 14534157, 23360469, 28488083, 32712949, 32770121, 20119593, 30202406) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 24, 2016	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2018

The p.R448* pathogenic mutation (also known as c.1342C>T), located in coding exon 13 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 1342. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in multiple families with neonatal and infantile seizures (Singh NA et al. Brain, 2003 Dec;126:2726-37; Yum MS et al. J. Korean Med. Sci., 2010 Feb;25:324-6; Zara F et al. Epilepsia, 2013 Mar;54:425-36; Grinton BE et al. Epilepsia, 2015 Jul;56:1071-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change creates a premature translational stop signal (p.Arg448*) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with benign familial neonatal-infantile seizures (PMID: 3360469, 20119593, 25982755). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21762). For these reasons, this variant has been classified as Pathogenic. -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

May 25, 2020

Truncating variant absent from gnomAD and recurrent in the litterature. -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Lifecell International Pvt. Ltd

-

A Heterozygous Nonsense variant c.1258C>T in Exon 11 of the KCNQ2 gene that results in the amino acid substitution p.Arg420* was identified. The observed variant has a maximum allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variation ID: 21762). The variant has been previously reported by Grinton BE et al, 2015. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Seizures, benign familial neonatal, 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

BFNIS (benign familial neonatal-infantile seizures) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
Vest4		0.96
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs118192226; hg19: chr20-62046439;