rs1057518621
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_004975.4(KCNB1):c.908G>A(p.Arg303Gln) 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
KCNB1
NM_004975.4 missense
NM_004975.4 missense
Scores
15
2
1
Clinical Significance
Conservation
PhyloP100: 7.91
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 Pathogenic. Variant got 17 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_004975.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, KCNB1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
?
Variant 20-49374652-C-T is Pathogenic according to our data. Variant chr20-49374652-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNB1 | NM_004975.4 | c.908G>A | p.Arg303Gln | missense_variant | 2/2 | ENST00000371741.6 | |
LOC105372649 | XR_001754659.2 | n.1201+42628C>T | intron_variant, non_coding_transcript_variant | ||||
KCNB1 | XM_011528799.3 | c.908G>A | p.Arg303Gln | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNB1 | ENST00000371741.6 | c.908G>A | p.Arg303Gln | missense_variant | 2/2 | 1 | NM_004975.4 | P1 | |
KCNB1 | ENST00000635465.1 | c.908G>A | p.Arg303Gln | missense_variant | 3/3 | 1 | P1 | ||
ENST00000637341.1 | n.206+42628C>T | intron_variant, non_coding_transcript_variant | 5 | ||||||
KCNB1 | ENST00000635878.1 | c.97-75269G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 26 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2020 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in an individual with features consistent with a KCNB1-related condition (Invitae). ClinVar contains an entry for this variant (Variation ID: 373805). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 303 of the KCNB1 protein (p.Arg303Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2016 | The R303Q variant in the KCNB1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R303Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R303Q 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R303Q variant is a strong candidate for a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Loss of catalytic residue at R303 (P = 0.1446);Loss of catalytic residue at R303 (P = 0.1446);
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