NM_004975.4:c.2473C>T

Variant names:

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

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]

KCNB1 links:

ENSG00000290421 (HGNC:):

ENSG00000290421 links:

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
KCNB1	NM_004975.4 link	c.2473C>T	p.Pro825Ser	missense_variant	Exon 2 of 2	ENST00000371741.6	NP_004966.1	Q14721
KCNB1	XM_011528799.3 link	c.2473C>T	p.Pro825Ser	missense_variant	Exon 3 of 3		XP_011527101.1	Q14721
LOC105372649	XR_001754659.2 link	n.1201+41063G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6 link	c.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.:

Cov.:

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.:

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.:

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.:

Cov.:

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.:

Bravo

AF:

0.0149

TwinsUK

AF:

0.0254

AC:

ALSPAC

AF:

0.0241

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0184

AC:

2230

Asia WGS

AF:

0.00202

AC:

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

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.065

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

.;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Uncertain

0.017

MutationAssessor

Benign

0.34

N;N

PrimateAI

Benign

0.34

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over