1-110603893-C-T

Variant summary

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

The NM_004974.4(KCNA2):​c.890G>A​(p.Arg297Gln) 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. 12/21 in silico tools predict a damaging 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. R297W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KCNA2
NM_004974.4 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
KCNA2 (HGNC:6220): (potassium voltage-gated channel subfamily A member 2) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1. [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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004974.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-110603894-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 986989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the KCNA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 3.831 (above the threshold of 3.09). Trascript score misZ: 5.1665 (above the threshold of 3.09). GenCC associations: The gene is linked to undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 32.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 1-110603893-C-T is Pathogenic according to our data. Variant chr1-110603893-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-110603893-C-T is described in Lovd as [Pathogenic]. Variant chr1-110603893-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNA2NM_004974.4 linkc.890G>A p.Arg297Gln missense_variant Exon 3 of 3 ENST00000316361.10 NP_004965.1 P16389-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNA2ENST00000316361.10 linkc.890G>A p.Arg297Gln missense_variant Exon 3 of 3 2 NM_004974.4 ENSP00000314520.4 P16389-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461890
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727246
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:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 32 Pathogenic:5
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 2015- -
Pathogenic, no assertion criteria providedresearchCenter of Excellence for Medical Genomics, Chulalongkorn UniversitySep 08, 2002- -
Pathogenic, criteria provided, single submitterclinical testing3billion, Medical GeneticsOct 02, 2021Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novoo in similarly affected unrelated individuals (PMID:25477152, 25751627, 27733563, PS2, PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Glu545Lys) has been reported as pathogenic (VCV000013655.18 PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.982, 3Cnet: 0.967, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterresearchMolecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella MarisJan 04, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 297 of the KCNA2 protein (p.Arg297Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant epileptic encephalopathy (PMID: 25477152, 25751627, 27733563). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190328). 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 KCNA2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 25751627). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 21, 2021Functional studies indicate a gain-of-function effect that disrupts normal function of the Kv1.2 potassium channel (Syrbe et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33802230, 31628766, 31692161, 30660924, 27535533, 31075689, 31487502, 31054490, 30283815, 29050392, 27733563, 25751627, 25477152) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2017- -
Developmental and epileptic encephalopathy, 1 Pathogenic:1Other:1
Likely pathogenic, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Pathogenic and reported on 12-31-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 26, 2016- -
Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de NantesFeb 18, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
35
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D;.;.;.;.;.;D;D;D;D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
.;D;D;D;D;T;.;.;.;D;D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.8
H;H;.;.;.;.;H;H;H;H;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.8
.;D;.;.;.;.;.;D;.;D;.
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
.;D;.;.;.;.;.;D;.;D;.
Sift4G
Pathogenic
0.0010
D;D;.;.;.;.;.;D;.;D;.
Polyphen
1.0
D;.;.;.;.;.;D;D;D;D;.
Vest4
0.93
MutPred
0.84
Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);.;.;.;.;Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);.;
MVP
0.99
MPC
2.5
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.94
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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: rs786205232; hg19: chr1-111146515; API