rs112735799

Positions:

chr20-49373723-G-A

Variant summary

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

The NM_004975.4(KCNB1):c.1837C>T(p.Pro613Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,128 control chromosomes in the GnomAD database, including 296 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 0.012 ( 14 hom., cov: 32)

Exomes 𝑓: 0.017 ( 282 hom. )

Consequence

KCNB1
NM_004975.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.83

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 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=0.003902465).

BP6

Variant 20-49373723-G-A is Benign according to our data. Variant chr20-49373723-G-A is described in ClinVar as [Benign]. Clinvar id is 383226.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 = 0.0122 (1860/152250) while in subpopulation NFE AF= 0.0186 (1262/68018). AF 95% confidence interval is 0.0177. There are 14 homozygotes in gnomad4. There are 873 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1860 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNB1	NM_004975.4 linkuse as main transcript	c.1837C>T	p.Pro613Ser	missense_variant	2/2	ENST00000371741.6	NP_004966.1	Q14721
KCNB1	XM_011528799.3 linkuse as main transcript	c.1837C>T	p.Pro613Ser	missense_variant	3/3		XP_011527101.1	Q14721
LOC105372649	XR_001754659.2 linkuse as main transcript	n.1201+41699G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNB1	ENST00000371741.6 linkuse as main transcript	c.1837C>T	p.Pro613Ser	missense_variant	2/2	1	NM_004975.4	ENSP00000360806.3	Q14721
KCNB1	ENST00000635465.1 linkuse as main transcript	c.1837C>T	p.Pro613Ser	missense_variant	3/3	1		ENSP00000489193.1	Q14721
KCNB1	ENST00000635878.1 linkuse as main transcript	c.97-74340C>T		intron_variant		5		ENSP00000489908.1	A0A1B0GU02
ENSG00000290421	ENST00000637341.1 linkuse as main transcript	n.206+41699G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1860

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00336

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00812

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0135

AC:

3378

AN:

251074

Hom.:

AF XY:

0.0133

AC XY:

1800

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.0100

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0274

Gnomad NFE exome

AF:

0.0198

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0173

AC:

25294

AN:

1461878

Hom.:

282

Cov.:

AF XY:

0.0166

AC XY:

12088

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00302

Gnomad4 AMR exome

AF:

0.0108

Gnomad4 ASJ exome

AF:

0.00386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0266

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0139

GnomAD4 genome

AF:

0.0122

AC:

1860

AN:

152250

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

873

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00335

Gnomad4 AMR

AF:

0.00811

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0265

Gnomad4 NFE

AF:

0.0186

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0163

Hom.:

Bravo

AF:

0.0115

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0189

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0177

AC:

152

ExAC

AF:

0.0141

AC:

1715

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0175

EpiControl

AF:

0.0175

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	Feb 20, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.67

.;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.29

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.11

Sift

Benign

0.11

T;.

Sift4G

Benign

0.11

T;T

Polyphen

0.0

B;B

Vest4

0.035

MPC

0.19

ClinPred

0.0060

GERP RS

1.2

Varity_R

0.048

gMVP

0.31

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