Genetic Variant NM_004975.4:c.567+20249T>G (chr20-49461665-A-C) – 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+20249T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 152,036 control chromosomes in the GnomAD database, including 9,434 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 0.35 ( 9434 hom., cov: 32)

Consequence

KCNB1
NM_004975.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.645

Publications

3 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:

ENSG00000302258 (HGNC:):

ENSG00000302258 links:

Genome browser will be placed here

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=-0.48).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4 link	c.567+20249T>G		intron_variant	Intron 1 of 1	ENST00000371741.6	NP_004966.1	Q14721
KCNB1	XM_011528799.3 link	c.567+20249T>G		intron_variant	Intron 2 of 2		XP_011527101.1	Q14721

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6 link	c.567+20249T>G		intron_variant	Intron 1 of 1	1	NM_004975.4	ENSP00000360806.3		Q14721

Frequencies

GnomAD3 genomes

AF:

0.346

AC:

52632

AN:

151918

Hom.:

9436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.276

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.478

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.323

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.390

Gnomad OTH

AF:

0.381

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

GnomAD4 genome

AF:

0.346

AC:

52637

AN:

152036

Hom.:

9434

Cov.:

AF XY:

0.344

AC XY:

25551

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.275

AC:

11416

AN:

41462

American (AMR)

AF:

0.372

AC:

5676

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.478

AC:

1660

AN:

3470

East Asian (EAS)

AF:

0.151

AC:

781

AN:

5186

South Asian (SAS)

AF:

0.322

AC:

1551

AN:

4812

European-Finnish (FIN)

AF:

0.363

AC:

3835

AN:

10574

Middle Eastern (MID)

AF:

0.449

AC:

132

AN:

294

European-Non Finnish (NFE)

AF:

0.390

AC:

26516

AN:

67950

Other (OTH)

AF:

0.378

AC:

796

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1746

3493

5239

6986

8732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.372

Hom.:

2642

Bravo

AF:

0.344

Asia WGS

AF:

0.224

AC:

777

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.65

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