rs864321707

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_172107.4(KCNQ2):​c.917C>T​(p.Ala306Val) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A306T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KCNQ2
NM_172107.4 missense

Scores

11
7
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:2

Conservation

PhyloP100: 7.88
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a helix (size 41) in uniprot entity KCNQ2_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) 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 chr20-63439609-C-T is described in Lovd as [Pathogenic].
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, 0.988
PP5
Variant 20-63439608-G-A is Pathogenic according to our data. Variant chr20-63439608-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 219235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63439608-G-A is described in Lovd as [Pathogenic]. Variant chr20-63439608-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ2NM_172107.4 linkc.917C>T p.Ala306Val missense_variant Exon 6 of 17 ENST00000359125.7 NP_742105.1 O43526-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ2ENST00000359125.7 linkc.917C>T p.Ala306Val missense_variant Exon 6 of 17 1 NM_172107.4 ENSP00000352035.2 O43526-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1460142
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726454
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.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 22, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This substitution is predicted to be within the transmembrane segment S6; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 27535030, 23708187, 32139178, 34120799, 29390993, 26704558, 25959266, 29455050, 31780880, 34055682, 29852413) -

Aug 04, 2022
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The KCNQ2 c.917C>T (p.Ala306Val) missense variant results in the substitution of alanine at amino acid position 306 with valine. This variant has been reported in at least seven individuals with an early onset epilepsy phenotype, including in one case also associated with sudden unexpected death (PMID: 29390993; PMID: 32139178; PMID: 29455050; PMID: 32917465; PMID: 27535030; PMID: 31780880; PMID: 25959266; PMID: 26704558; PMID: 29852413; PMID: 34120799; PMID: 34055682). In four of these individuals the variant was reported to have occurred de novo (PMID: 34120799; PMID: 29852413; PMID: 27535030; PMID: 29390993). Another variant at the same amino acid position, c.916G>A p.Ala306Thr, has been reported in a heterozygous state in three probands, two with benign familial neonatal convulsions, both individuals inheriting the variant from affected parents (PMID: 9425895; PMID: 24375629). In the third proband the p.Ala306Thr variant was reported to have occurred de novo in a male child with infantile spasm, developmental delay and hypotonia but without epileptic seizures (PMID: 26138355). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.917C>T (p.Ala306Val) variant is classified as pathogenic for KCNQ2-related disorders. -

Developmental and epileptic encephalopathy, 7 Pathogenic:2Other:1
-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense variant p.A306V in KCNQ2 (NM_172107.4) has been reported in multiple individuals with Otahara syndrome, wherein it was proved to be de novo in some patients(Rim JH et al,Hortigüela M et al). The variant has been submitted to ClinVar as Pathogenic.The p.A306V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.A306V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 306 of KCNQ2 is conserved in all mammalian species. The nucleotide c.917 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

-
NeuroMeGen, Hospital Clinico Santiago de Compostela
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

EE (epileptic encephalopathy) -

KCNQ2-related disorder Pathogenic:1
Sep 29, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: KCNQ2 c.917C>T (p.Ala306Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250792 control chromosomes. c.917C>T has been reported in the literature in individuals affected with early onset epileptic encephalopathy and Ohtahara syndrome, and in multiple cases was reported as a de novo variant (Ko_2018, Kothur_2018, Fernandez-Marmiesse_2018, Sun_2021, Shellhaas_2017, Bagnall_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting codon 306 have been reported in association with Epilepsy and/or neurodevelopmental disorders in HGMD (A306P, A306T). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Oct 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the KCNQ2 protein (p.Ala306Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset epileptic encephalopathy and Ohtahara syndrome (PMID: 25959266, 26704558, 27535030, 29390993). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219235). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. This variant disrupts the p.Ala306 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425895, 19453707, 26138355). 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. -

Autosomal recessive congenital ichthyosis 10 Pathogenic:1
-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense variant p.S53W in PNPLA1 (NM_001145717.1) has been previously reported in homozygous state in an affected patient. The patient had a collodion membrane at birth (Boyden LM et al).The variant has been submitted to ClinVar as Pathogenic based on the same. The p.S53W variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between serine and tryptophan, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. For these reasons, this variant has been classified as Likely Pathogenic. -

Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Pathogenic:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Complex neurodevelopmental disorder Other:1
-
Channelopathy-Associated Epilepsy Research Center
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
.;.;D;D;D;T;D;D;.;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H;.;.;.;.;.;H;.;H;H;H
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.5
.;.;.;.;D;.;D;.;D;D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
.;.;.;.;D;.;D;.;D;D;D
Sift4G
Uncertain
0.026
D;D;D;D;D;.;D;D;D;D;D
Polyphen
0.99
D;.;.;.;.;.;D;.;D;D;.
Vest4
0.97
MutPred
0.90
Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);.;Loss of catalytic residue at A306 (P = 0.4461);.;Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);
MVP
0.99
MPC
2.8
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.90
gMVP
1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs864321707; hg19: chr20-62070961; COSMIC: COSV60436134; COSMIC: COSV60436134; API