rs761082551
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2
The NM_004975.4(KCNB1):c.1367G>A(p.Arg456Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,614,042 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
KCNB1
NM_004975.4 missense
NM_004975.4 missense
Scores
6
6
7
Clinical Significance
Conservation
PhyloP100: 3.39
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 Benign. Variant got -17 ACMG points.
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=0.23682433).
BP6
Variant 20-49374193-C-T is Benign according to our data. Variant chr20-49374193-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 385978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000226 (331/1461850) while in subpopulation NFE AF= 0.000288 (320/1111996). AF 95% confidence interval is 0.000262. There are 0 homozygotes in gnomad4_exome. There are 166 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNB1 | NM_004975.4 | c.1367G>A | p.Arg456Gln | missense_variant | 2/2 | ENST00000371741.6 | NP_004966.1 | |
KCNB1 | XM_011528799.3 | c.1367G>A | p.Arg456Gln | missense_variant | 3/3 | XP_011527101.1 | ||
LOC105372649 | XR_001754659.2 | n.1201+42169C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNB1 | ENST00000371741.6 | c.1367G>A | p.Arg456Gln | missense_variant | 2/2 | 1 | NM_004975.4 | ENSP00000360806.3 | ||
KCNB1 | ENST00000635465.1 | c.1367G>A | p.Arg456Gln | missense_variant | 3/3 | 1 | ENSP00000489193.1 | |||
KCNB1 | ENST00000635878.1 | c.97-74810G>A | intron_variant | 5 | ENSP00000489908.1 | |||||
ENSG00000290421 | ENST00000637341.1 | n.206+42169C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000115 AC: 29AN: 251384Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135850
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GnomAD4 exome AF: 0.000226 AC: 331AN: 1461850Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 166AN XY: 727222
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74350
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | KCNB1: BP5, BS1:Supporting - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2021 | - - |
Developmental and epileptic encephalopathy, 26 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
KCNB1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 21, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
PrimateAI
Benign
T
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Benign
D;.
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at