rs144379782

Variant summary

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

The NM_004975.4(KCNB1):c.2105C>T(p.Ala702Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A702E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

KCNB1
NM_004975.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.32

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:

(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 where missense usually causes diseases, KCNB1

BP4

Computational evidence support a benign effect (MetaRNN=0.035757184).

BP6

Variant 20-49373455-G-A is Benign according to our data. Variant chr20-49373455-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 762094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000657 (10/152136) while in subpopulation EAS AF= 0.000962 (5/5196). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNB1	NM_004975.4 linkuse as main transcript	c.2105C>T	p.Ala702Val	missense_variant	2/2	ENST00000371741.6
LOC105372649	XR_001754659.2 linkuse as main transcript	n.1201+41431G>A		intron_variant, non_coding_transcript_variant
KCNB1	XM_011528799.3 linkuse as main transcript	c.2105C>T	p.Ala702Val	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KCNB1	ENST00000371741.6 linkuse as main transcript	c.2105C>T	p.Ala702Val	missense_variant	2/2	1	NM_004975.4	P1
KCNB1	ENST00000635465.1 linkuse as main transcript	c.2105C>T	p.Ala702Val	missense_variant	3/3	1		P1
	ENST00000637341.1 linkuse as main transcript	n.206+41431G>A		intron_variant, non_coding_transcript_variant		5
KCNB1	ENST00000635878.1 linkuse as main transcript	c.97-74072C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250842

Hom.:

AF XY:

0.0000959

AC XY:

AN XY:

135614

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000731

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000962

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.46

Cadd

Benign

Dann

Benign

0.59

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-0.074

Eigen_PC

Benign

0.036

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.011

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

0.82

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.15

N;.

REVEL

Benign

0.14

Sift

Benign

0.29

T;.

Sift4G

Benign

0.34

T;T

Polyphen

0.72

P;P

Vest4

0.27

MVP

0.38

MPC

0.24

ClinPred

0.058

GERP RS

4.8

Varity_R

0.074

gMVP

0.35

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