rs1355278265

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_004975.4(KCNB1):​c.1727C>G​(p.Thr576Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T576K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNB1
NM_004975.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16
Variant links:
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNB1. . Gene score misZ 4.269 (greater than the threshold 3.09). Trascript score misZ 5.3923 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 26.
BP4
Computational evidence support a benign effect (MetaRNN=0.14308149).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNB1NM_004975.4 linkuse as main transcriptc.1727C>G p.Thr576Arg missense_variant 2/2 ENST00000371741.6
LOC105372649XR_001754659.2 linkuse as main transcriptn.1201+41809G>C intron_variant, non_coding_transcript_variant
KCNB1XM_011528799.3 linkuse as main transcriptc.1727C>G p.Thr576Arg missense_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNB1ENST00000371741.6 linkuse as main transcriptc.1727C>G p.Thr576Arg missense_variant 2/21 NM_004975.4 P1
KCNB1ENST00000635465.1 linkuse as main transcriptc.1727C>G p.Thr576Arg missense_variant 3/31 P1
ENST00000637341.1 linkuse as main transcriptn.206+41809G>C intron_variant, non_coding_transcript_variant 5
KCNB1ENST00000635878.1 linkuse as main transcriptc.97-74450C>G intron_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
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, 26 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 02, 2021In 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 KCNB1 protein function. This variant has not been reported in the literature in individuals affected with KCNB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 576 of the KCNB1 protein (p.Thr576Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
21
DANN
Benign
0.95
DEOGEN2
Benign
0.20
T;T
Eigen
Benign
-0.086
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.63
.;T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.14
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.44
N;N
MutationTaster
Benign
0.73
D
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.48
N;.
REVEL
Benign
0.14
Sift
Benign
0.30
T;.
Sift4G
Benign
0.61
T;T
Polyphen
0.0
B;B
Vest4
0.065
MutPred
0.46
Loss of glycosylation at T576 (P = 0.0218);Loss of glycosylation at T576 (P = 0.0218);
MVP
0.22
MPC
0.21
ClinPred
0.83
D
GERP RS
6.1
Varity_R
0.16
gMVP
0.37

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: chr20-47990370; API