Genetic Variant NM_014002.4:c.2138C>T (chr1-206496132-C-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_014002.4(IKBKE):c.2138C>T(p.Pro713Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,610,104 control chromosomes in the GnomAD database, including 36,569 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2877 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33692 hom. )

Consequence

IKBKE
NM_014002.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.15

Publications

47 publications found

Variant links:

Genes affected

IKBKE (HGNC:14552): (inhibitor of nuclear factor kappa B kinase subunit epsilon) IKBKE is a noncanonical I-kappa-B (see MIM 164008) kinase (IKK) that is essential for regulating antiviral signaling pathways. IKBKE has also been identified as a breast cancer (MIM 114480) oncogene and is amplified and overexpressed in over 30% of breast carcinomas and breast cancer cell lines (Hutti et al., 2009 [PubMed 19481526]).[supplied by OMIM, Oct 2009]

IKBKE links:

IKBKE-AS1 (HGNC:32061): (IKBKE antisense RNA 1)

IKBKE-AS1 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 (MetaRNN=0.0047554076).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKE	NM_014002.4 link	c.2138C>T	p.Pro713Leu	missense_variant	Exon 22 of 22	ENST00000581977.7	NP_054721.1	Q14164-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IKBKE	ENST00000581977.7 link	c.2138C>T	p.Pro713Leu	missense_variant	Exon 22 of 22	1	NM_014002.4	ENSP00000464030.1	Q14164-1
IKBKE	ENST00000584998.5 link	c.1883C>T	p.Pro628Leu	missense_variant	Exon 21 of 21	1		ENSP00000462396.1	Q14164-2
IKBKE	ENST00000578328.6 link	c.*51C>T		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000473833.1	A0A075B7B4
IKBKE-AS1	ENST00000367119.1 link	n.135+1462G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26174

AN:

151970

Hom.:

2880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0430

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.0921

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.223

Gnomad OTH

AF:

0.206

GnomAD2 exomes

AF:

0.199

AC:

50019

AN:

250932

AF XY:

0.197

show subpopulations

Gnomad AFR exome

AF:

0.0358

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.216

Gnomad FIN exome

AF:

0.259

Gnomad NFE exome

AF:

0.223

Gnomad OTH exome

AF:

0.210

GnomAD4 exome

AF:

0.209

AC:

304607

AN:

1458016

Hom.:

33692

Cov.:

AF XY:

0.206

AC XY:

149280

AN XY:

725496

show subpopulations

African (AFR)

AF:

0.0364

AC:

1217

AN:

33458

American (AMR)

AF:

0.272

AC:

12170

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

3723

AN:

26100

East Asian (EAS)

AF:

0.190

AC:

7523

AN:

39662

South Asian (SAS)

AF:

0.0888

AC:

7656

AN:

86170

European-Finnish (FIN)

AF:

0.255

AC:

13596

AN:

53398

Middle Eastern (MID)

AF:

0.202

AC:

1163

AN:

5748

European-Non Finnish (NFE)

AF:

0.222

AC:

245559

AN:

1108534

Other (OTH)

AF:

0.199

AC:

12000

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

10873

21746

32620

43493

54366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8304

16608

24912

33216

41520

<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:

0.172

AC:

26170

AN:

152088

Hom.:

2877

Cov.:

AF XY:

0.175

AC XY:

13023

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0428

AC:

1778

AN:

41518

American (AMR)

AF:

0.243

AC:

3707

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

546

AN:

3470

East Asian (EAS)

AF:

0.200

AC:

1031

AN:

5160

South Asian (SAS)

AF:

0.0924

AC:

446

AN:

4826

European-Finnish (FIN)

AF:

0.268

AC:

2831

AN:

10564

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.223

AC:

15124

AN:

67966

Other (OTH)

AF:

0.204

AC:

431

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1084

2168

3252

4336

5420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

280

560

840

1120

1400

<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:

0.203

Hom.:

11822

Bravo

AF:

0.169

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.232

AC:

896

ESP6500AA

AF:

0.0443

AC:

195

ESP6500EA

AF:

0.218

AC:

1876

ExAC

AF:

0.193

AC:

23436

Asia WGS

AF:

0.118

AC:

410

AN:

3478

EpiCase

AF:

0.221

EpiControl

AF:

0.216

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.042

.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L

PhyloP100

2.1

PrimateAI

Benign

0.30

Sift4G

Benign

0.47

T;T

Polyphen

0.030

.;B

Vest4

0.097

ClinPred

0.0080

GERP RS

3.5

Varity_R

0.050

gMVP

0.075

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over