dbSNP rs115698972: IKBKB:p.Glu502Lys (chr8-42319409-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001556.3(IKBKB):c.1504G>A(p.Glu502Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000584 in 1,614,174 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 4 hom. )

Consequence

IKBKB
NM_001556.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.58

Publications

2 publications found

Variant links:

Genes affected

IKBKB (HGNC:5960): (inhibitor of nuclear factor kappa B kinase subunit beta) The protein encoded by this gene phosphorylates the inhibitor in the inhibitor/NF-kappa-B complex, causing dissociation of the inhibitor and activation of NF-kappa-B. The encoded protein itself is found in a complex of proteins. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Sep 2011]

IKBKB Gene-Disease associations (from GenCC):

severe combined immunodeficiency due to IKK2 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen
immunodeficiency 15a
Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

IKBKB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00725773).

BP6

Variant 8-42319409-G-A is Benign according to our data. Variant chr8-42319409-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541644.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00311 (474/152282) while in subpopulation AFR AF = 0.0109 (454/41554). AF 95% confidence interval is 0.0101. There are 0 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001556.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IKBKB	NM_001556.3	MANE Select	c.1504G>A	p.Glu502Lys	missense	Exon 14 of 22	NP_001547.1	O14920-1
IKBKB	NM_001242778.2		c.1327G>A	p.Glu443Lys	missense	Exon 13 of 21	NP_001229707.1	O14920-4
IKBKB	NM_001190720.3		c.1312G>A	p.Glu438Lys	missense	Exon 13 of 21	NP_001177649.2	A0A499FJS7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.1504G>A	p.Glu502Lys	missense	Exon 14 of 22	ENSP00000430684.1	O14920-1
IKBKB	ENST00000523517.5	TSL:1	n.*323G>A		non_coding_transcript_exon	Exon 13 of 21	ENSP00000430114.1	E5RGW5
IKBKB	ENST00000523517.5	TSL:1	n.*323G>A		3_prime_UTR	Exon 13 of 21	ENSP00000430114.1	E5RGW5

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

474

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000760

AC:

191

AN:

251456

AF XY:

0.000559

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000321

AC:

469

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

202

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0122

AC:

407

AN:

33480

American (AMR)

AF:

0.000492

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112010

Other (OTH)

AF:

0.000563

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00311

AC:

474

AN:

152282

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

211

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0109

AC:

454

AN:

41554

American (AMR)

AF:

0.000850

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00117

Hom.:

Bravo

AF:

0.00361

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000931

AC:

113

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

IKBKB-related disorder (1)

Inborn genetic diseases (1)

Severe combined immunodeficiency due to IKK2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

0.058

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.3

PhyloP100

4.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.010

REVEL

Benign

0.13

Sift

Benign

0.53

Sift4G

Benign

0.58

Polyphen

0.067

Vest4

0.34

MVP

0.75

MPC

0.57

ClinPred

0.012

GERP RS

6.0

Varity_R

0.35

gMVP

0.25

Mutation Taster

=95/5

polymorphism

(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