20-49373713-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004975.4(KCNB1):c.1847C>G(p.Thr616Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0183 in 1,614,164 control chromosomes in the GnomAD database, including 328 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T616I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.015 ( 19 hom., cov: 32)

Exomes 𝑓: 0.019 ( 309 hom. )

Consequence

KCNB1
NM_004975.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.96

Publications

11 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNB1 links:

ENSG00000290421 (HGNC:):

ENSG00000290421 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023046434).

BP6

Variant 20-49373713-G-C is Benign according to our data. Variant chr20-49373713-G-C is described in ClinVar as Benign. ClinVar VariationId is 380823.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 = 0.0155 (2359/152282) while in subpopulation NFE AF = 0.0211 (1438/68014). AF 95% confidence interval is 0.0202. There are 19 homozygotes in GnomAd4. There are 1215 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2359 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004975.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNB1	NM_004975.4	MANE Select	c.1847C>G	p.Thr616Ser	missense	Exon 2 of 2	NP_004966.1	Q14721

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNB1	ENST00000371741.6	TSL:1 MANE Select	c.1847C>G	p.Thr616Ser	missense	Exon 2 of 2	ENSP00000360806.3	Q14721
KCNB1	ENST00000635465.1	TSL:1	c.1847C>G	p.Thr616Ser	missense	Exon 3 of 3	ENSP00000489193.1	Q14721
KCNB1	ENST00000635878.1	TSL:5	c.97-74330C>G		intron	N/A	ENSP00000489908.1	A0A1B0GU02

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

2361

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00357

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0193

Gnomad FIN

AF:

0.0329

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0154

GnomAD2 exomes

AF:

0.0173

AC:

4347

AN:

250860

AF XY:

0.0183

show subpopulations

Gnomad AFR exome

AF:

0.00266

Gnomad AMR exome

AF:

0.00841

Gnomad ASJ exome

AF:

0.0290

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0365

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0186

AC:

27151

AN:

1461882

Hom.:

309

Cov.:

AF XY:

0.0190

AC XY:

13810

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

33480

American (AMR)

AF:

0.00888

AC:

397

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0275

AC:

719

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0206

AC:

1781

AN:

86258

European-Finnish (FIN)

AF:

0.0315

AC:

1682

AN:

53418

Middle Eastern (MID)

AF:

0.0179

AC:

103

AN:

5768

European-Non Finnish (NFE)

AF:

0.0191

AC:

21260

AN:

1112002

Other (OTH)

AF:

0.0186

AC:

1126

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1669

3338

5006

6675

8344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

798

1596

2394

3192

3990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0155

AC:

2359

AN:

152282

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1215

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00356

AC:

148

AN:

41558

American (AMR)

AF:

0.0127

AC:

195

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0189

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0329

AC:

349

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0211

AC:

1438

AN:

68014

Other (OTH)

AF:

0.0152

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

113

226

339

452

565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0188

Hom.:

Bravo

AF:

0.0125

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0189

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0197

AC:

169

ExAC

AF:

0.0162

AC:

1969

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0208

EpiControl

AF:

0.0211

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Developmental and epileptic encephalopathy, 26 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.20

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

5.0

PrimateAI

Benign

0.40

PROVEAN

Benign

0.44

REVEL

Benign

0.11

Sift

Benign

0.71

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.047

MutPred

0.090

Gain of glycosylation at T616 (P = 0.0255)

MPC

0.17

ClinPred

0.0064

GERP RS

5.0

Varity_R

0.057

gMVP

0.18

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over