rs34467662

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004975.4(KCNB1):​c.2473C>T​(p.Pro825Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0222 in 1,614,094 control chromosomes in the GnomAD database, including 569 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 39 hom., cov: 32)
Exomes 𝑓: 0.023 ( 530 hom. )

Consequence

KCNB1
NM_004975.4 missense

Scores

1
1
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in the KCNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 76 curated pathogenic missense variants (we use a threshold of 10). The gene has 110 curated benign missense variants. Gene score misZ: 4.269 (above the threshold of 3.09). Trascript score misZ: 5.3923 (above the threshold of 3.09). GenCC associations: The gene is linked to undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 26.
BP4
Computational evidence support a benign effect (MetaRNN=0.003086567).
BP6
Variant 20-49373087-G-A is Benign according to our data. Variant chr20-49373087-G-A is described in ClinVar as [Benign]. Clinvar id is 382142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0178 (2710/152214) while in subpopulation NFE AF= 0.0291 (1980/68018). AF 95% confidence interval is 0.028. There are 39 homozygotes in gnomad4. There are 1261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 2710 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNB1NM_004975.4 linkc.2473C>T p.Pro825Ser missense_variant Exon 2 of 2 ENST00000371741.6 NP_004966.1 Q14721
KCNB1XM_011528799.3 linkc.2473C>T p.Pro825Ser missense_variant Exon 3 of 3 XP_011527101.1 Q14721
LOC105372649XR_001754659.2 linkn.1201+41063G>A intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNB1ENST00000371741.6 linkc.2473C>T p.Pro825Ser missense_variant Exon 2 of 2 1 NM_004975.4 ENSP00000360806.3 Q14721

Frequencies

GnomAD3 genomes
AF:
0.0178
AC:
2711
AN:
152096
Hom.:
39
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00357
Gnomad AMI
AF:
0.0296
Gnomad AMR
AF:
0.00681
Gnomad ASJ
AF:
0.0196
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00373
Gnomad FIN
AF:
0.0325
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0291
Gnomad OTH
AF:
0.00956
GnomAD3 exomes
AF:
0.0181
AC:
4541
AN:
251462
Hom.:
77
AF XY:
0.0183
AC XY:
2487
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00283
Gnomad AMR exome
AF:
0.00578
Gnomad ASJ exome
AF:
0.0178
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00438
Gnomad FIN exome
AF:
0.0321
Gnomad NFE exome
AF:
0.0278
Gnomad OTH exome
AF:
0.0196
GnomAD4 exome
AF:
0.0227
AC:
33180
AN:
1461880
Hom.:
530
Cov.:
32
AF XY:
0.0223
AC XY:
16252
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00275
Gnomad4 AMR exome
AF:
0.00595
Gnomad4 ASJ exome
AF:
0.0183
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00423
Gnomad4 FIN exome
AF:
0.0313
Gnomad4 NFE exome
AF:
0.0260
Gnomad4 OTH exome
AF:
0.0218
GnomAD4 genome
AF:
0.0178
AC:
2710
AN:
152214
Hom.:
39
Cov.:
32
AF XY:
0.0169
AC XY:
1261
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.00356
Gnomad4 AMR
AF:
0.00680
Gnomad4 ASJ
AF:
0.0196
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.00352
Gnomad4 FIN
AF:
0.0325
Gnomad4 NFE
AF:
0.0291
Gnomad4 OTH
AF:
0.00946
Alfa
AF:
0.0245
Hom.:
64
Bravo
AF:
0.0149
TwinsUK
AF:
0.0254
AC:
94
ALSPAC
AF:
0.0241
AC:
93
ESP6500AA
AF:
0.00386
AC:
17
ESP6500EA
AF:
0.0281
AC:
242
ExAC
AF:
0.0184
AC:
2230
Asia WGS
AF:
0.00202
AC:
8
AN:
3478
EpiCase
AF:
0.0253
EpiControl
AF:
0.0236

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Dec 20, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Developmental and epileptic encephalopathy, 26 Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
Jan 14, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
18
DANN
Benign
0.89
DEOGEN2
Benign
0.23
T;T
Eigen
Benign
-0.065
Eigen_PC
Benign
0.13
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.73
.;T
MetaRNN
Benign
0.0031
T;T
MetaSVM
Uncertain
0.017
D
MutationAssessor
Benign
0.34
N;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
0.46
N;.
REVEL
Benign
0.27
Sift
Benign
0.22
T;.
Sift4G
Benign
0.53
T;T
Polyphen
0.0020
B;B
Vest4
0.11
MPC
0.19
ClinPred
0.019
T
GERP RS
4.6
Varity_R
0.095
gMVP
0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34467662; hg19: chr20-47989624; API