NM_004975.4:c.1388T>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_004975.4(KCNB1):c.1388T>C(p.Ile463Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,614,084 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 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

KCNB1
NM_004975.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 9.32

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 -13 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=0.0869675).

BP6

Variant 20-49374172-A-G is Benign according to our data. Variant chr20-49374172-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 475257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4 link	c.1388T>C	p.Ile463Thr	missense_variant	Exon 2 of 2	ENST00000371741.6	NP_004966.1	Q14721
KCNB1	XM_011528799.3 link	c.1388T>C	p.Ile463Thr	missense_variant	Exon 3 of 3		XP_011527101.1	Q14721
LOC105372649	XR_001754659.2 link	n.1201+42148A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNB1	ENST00000371741.6 link	c.1388T>C	p.Ile463Thr	missense_variant	Exon 2 of 2	1	NM_004975.4	ENSP00000360806.3	Q14721
KCNB1	ENST00000635465.1 link	c.1388T>C	p.Ile463Thr	missense_variant	Exon 3 of 3	1		ENSP00000489193.1	Q14721
KCNB1	ENST00000635878.1 link	c.97-74789T>C		intron_variant	Intron 1 of 2	5		ENSP00000489908.1	A0A1B0GU02
ENSG00000290421	ENST00000637341.1 link	n.206+42148A>G		intron_variant	Intron 2 of 7	5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251430

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.000761

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000992

AC:

145

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000803

Gnomad4 EAS exome

AF:

0.00166

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 26

Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Aug 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31875159) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

.;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.087

T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

D;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.011

D;D

Polyphen

0.61

P;P

Vest4

0.57

MVP

0.67

MPC

0.31

ClinPred

0.24

GERP RS

6.1

Varity_R

0.39

gMVP

0.41

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