20-49372990-C-T

Position:

chr20-49372990-C-T

Variant summary

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

The NM_004975.4(KCNB1):c.2570G>A(p.Ser857Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,608,510 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 10 hom., cov: 32)

Exomes 𝑓: 0.011 ( 132 hom. )

Consequence

KCNB1
NM_004975.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.92

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:

(HGNC:):

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 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=0.0059853196).

BP6

Variant 20-49372990-C-T is Benign according to our data. Variant chr20-49372990-C-T is described in ClinVar as [Benign]. Clinvar id is 380824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-49372990-C-T is described in Lovd as [Likely_benign]. Variant chr20-49372990-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00921 (1402/152192) while in subpopulation NFE AF= 0.0122 (829/67998). AF 95% confidence interval is 0.0115. There are 10 homozygotes in gnomad4. There are 762 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNB1	NM_004975.4 linkuse as main transcript	c.2570G>A	p.Ser857Asn	missense_variant	2/2	ENST00000371741.6
LOC105372649	XR_001754659.2 linkuse as main transcript	n.1201+40966C>T		intron_variant, non_coding_transcript_variant
KCNB1	XM_011528799.3 linkuse as main transcript	c.2570G>A	p.Ser857Asn	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNB1	ENST00000371741.6 linkuse as main transcript	c.2570G>A	p.Ser857Asn	missense_variant	2/2	1	NM_004975.4	P1
	ENST00000637341.1 linkuse as main transcript	n.206+40966C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00922

AC:

1402

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00643

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.0288

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.0102

AC:

2519

AN:

245830

Hom.:

AF XY:

0.0110

AC XY:

1459

AN XY:

132836

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00391

Gnomad ASJ exome

AF:

0.00852

Gnomad EAS exome

AF:

0.000166

Gnomad SAS exome

AF:

0.0115

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00886

GnomAD4 exome

AF:

0.0108

AC:

15744

AN:

1456318

Hom.:

132

Cov.:

AF XY:

0.0110

AC XY:

8004

AN XY:

724384

show subpopulations

Gnomad4 AFR exome

AF:

0.00150

Gnomad4 AMR exome

AF:

0.00392

Gnomad4 ASJ exome

AF:

0.00915

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0121

Gnomad4 FIN exome

AF:

0.0261

Gnomad4 NFE exome

AF:

0.0110

Gnomad4 OTH exome

AF:

0.00970

GnomAD4 genome

AF:

0.00921

AC:

1402

AN:

152192

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

762

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00169

Gnomad4 AMR

AF:

0.00642

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.0288

Gnomad4 NFE

AF:

0.0122

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00989

Hom.:

Bravo

AF:

0.00677

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00968

AC:

1175

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KCNB1: BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2016

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. -

Developmental and epileptic encephalopathy, 26

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.43

.;T

MetaRNN

Benign

0.0060

T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

0.97

L;L

MutationTaster

Benign

0.77

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.53

N;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.013

D;D

Polyphen

0.98

D;D

Vest4

0.095

MPC

0.17

ClinPred

0.023

GERP RS

3.1

Varity_R

0.13

gMVP

0.61

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