rs200499541

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_004974.4(KCNA2):​c.372G>C​(p.Glu124Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E124E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNA2
NM_004974.4 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.3087129).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNA2NM_004974.4 linkc.372G>C p.Glu124Asp 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.372G>C p.Glu124Asp missense_variant Exon 3 of 3 2 NM_004974.4 ENSP00000314520.4 P16389-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 32 Uncertain:1
Nov 16, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt KCNA2 protein function. This variant has not been reported in the literature in individuals affected with KCNA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 124 of the KCNA2 protein (p.Glu124Asp). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.066
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D;.;D;D;D;D;.
Eigen
Benign
-0.19
Eigen_PC
Benign
0.025
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.78
.;T;.;.;.;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.31
T;T;T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.0
L;L;L;L;L;L;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.4
.;N;.;N;.;N;.
REVEL
Uncertain
0.30
Sift
Benign
0.20
.;T;.;T;.;T;.
Sift4G
Benign
0.20
T;T;.;T;.;T;.
Polyphen
0.0070
B;.;B;B;B;B;.
Vest4
0.63
MutPred
0.46
Loss of disorder (P = 0.123);Loss of disorder (P = 0.123);Loss of disorder (P = 0.123);Loss of disorder (P = 0.123);Loss of disorder (P = 0.123);Loss of disorder (P = 0.123);.;
MVP
0.93
MPC
2.2
ClinPred
0.73
D
GERP RS
5.1
Varity_R
0.28
gMVP
0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-111147033; API