Genetic Variant KCNB1:c.567+12149T>A (chr20-49469765-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004975.4(KCNB1):c.567+12149T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 151,926 control chromosomes in the GnomAD database, including 2,439 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2439 hom., cov: 32)

Consequence

KCNB1
NM_004975.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.669

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 26
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4 link	c.567+12149T>A		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3 link	c.567+12149T>A		intron_variant	Intron 2 of 2		XP_011527101.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
KCNB1	ENST00000371741.6 link	c.567+12149T>A	intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3
KCNB1	ENST00000635465.1 link	c.567+12149T>A	intron_variant	Intron 2 of 2	1		ENSP00000489193.1
KCNB1	ENST00000635878.1 link	c.96+12149T>A	intron_variant	Intron 1 of 2	5		ENSP00000489908.1
KCNB1	ENST00000636950.1 link	n.87+12149T>A	intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23833

AN:

151810

Hom.:

2425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.286

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.144

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.135

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.157

AC:

23879

AN:

151926

Hom.:

2439

Cov.:

AF XY:

0.156

AC XY:

11601

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.286

AC:

11838

AN:

41380

American (AMR)

AF:

0.144

AC:

2194

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

128

AN:

3470

East Asian (EAS)

AF:

0.119

AC:

617

AN:

5170

South Asian (SAS)

AF:

0.102

AC:

493

AN:

4818

European-Finnish (FIN)

AF:

0.119

AC:

1255

AN:

10510

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.103

AC:

6978

AN:

67978

Other (OTH)

AF:

0.134

AC:

283

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

934

1868

2801

3735

4669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.130

Hom.:

210

Bravo

AF:

0.166

Asia WGS

AF:

0.107

AC:

370

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.89

(source)

DANN

Benign

0.81

PhyloP100

-0.67

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over