Genetic Variant IKBKB:c.-18-96A>G (chr8-42271987-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_001556.3(IKBKB):c.-18-96A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,260,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00076 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

IKBKB
NM_001556.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.25

Publications

23 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, ClinGen, Ambry Genetics
immunodeficiency 15a
Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

IKBKB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000755 (115/152220) while in subpopulation AFR AF = 0.00265 (110/41566). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKB	NM_001556.3 link	c.-18-96A>G		intron_variant	Intron 1 of 21	ENST00000520810.6	NP_001547.1	O14920-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6 link	c.-18-96A>G		intron_variant	Intron 1 of 21	1	NM_001556.3	ENSP00000430684.1		O14920-1

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD4 exome

AF:

0.0000659

AC:

AN:

1107930

Hom.:

Cov.:

AF XY:

0.0000668

AC XY:

AN XY:

553496

show subpopulations

African (AFR)

AF:

0.00256

AC:

AN:

24594

American (AMR)

AF:

0.00

AC:

AN:

26870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18388

East Asian (EAS)

AF:

0.00

AC:

AN:

37418

South Asian (SAS)

AF:

0.00

AC:

AN:

63578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3322

European-Non Finnish (NFE)

AF:

0.00000716

AC:

AN:

838236

Other (OTH)

AF:

0.0000843

AC:

AN:

47424

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152220

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67992

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

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:

0.00

Hom.:

1051

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.067

(source)

DANN

Benign

0.58

PhyloP100

-1.3

PromoterAI

0.043

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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