rs1131691752
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_004975.4(KCNB1):āc.2392G>Cā(p.Glu798Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
KCNB1
NM_004975.4 missense
NM_004975.4 missense
Scores
2
9
7
Clinical Significance
Conservation
PhyloP100: 5.32
Genes affected
KCNB1 (HGNC:6231): (potassium voltage-gated channel subfamily B member 1) Voltage-gated potassium (Kv) 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, shab-related subfamily. This member is a delayed rectifier potassium channel and its activity is modulated by some other family members. [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 where missense usually causes diseases, KCNB1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.28861022).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNB1 | NM_004975.4 | c.2392G>C | p.Glu798Gln | missense_variant | 2/2 | ENST00000371741.6 | |
LOC105372649 | XR_001754659.2 | n.1201+41144C>G | intron_variant, non_coding_transcript_variant | ||||
KCNB1 | XM_011528799.3 | c.2392G>C | p.Glu798Gln | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNB1 | ENST00000371741.6 | c.2392G>C | p.Glu798Gln | missense_variant | 2/2 | 1 | NM_004975.4 | P1 | |
KCNB1 | ENST00000635465.1 | c.2392G>C | p.Glu798Gln | missense_variant | 3/3 | 1 | P1 | ||
ENST00000637341.1 | n.206+41144C>G | intron_variant, non_coding_transcript_variant | 5 | ||||||
KCNB1 | ENST00000635878.1 | c.97-73785G>C | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 exome
AF:
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4
AN:
1461888
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
727246
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 26 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2020 | Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with KCNB1-related disease. ClinVar contains an entry for this variant (Variation ID: 430043). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 798 of the KCNB1 protein (p.Glu798Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 15, 2017 | The E798Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E798Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with KCNB1-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Benign
T;.
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MutPred
Loss of catalytic residue at E798 (P = 0.0866);Loss of catalytic residue at E798 (P = 0.0866);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at