Genetic Variant IKBKB:p.Gln743Arg (chr8-42330936-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001556.3(IKBKB):c.2228A>G(p.Gln743Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q743L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IKBKB
NM_001556.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.92

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10410881).

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.2228A>G	p.Gln743Arg	missense	Exon 22 of 22	NP_001547.1	O14920-1
IKBKB	NM_001242778.2		c.2051A>G	p.Gln684Arg	missense	Exon 21 of 21	NP_001229707.1	O14920-4
IKBKB	NM_001190720.3		c.2036A>G	p.Gln679Arg	missense	Exon 21 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.2228A>G	p.Gln743Arg	missense	Exon 22 of 22	ENSP00000430684.1	O14920-1
IKBKB	ENST00000523517.5	TSL:1	n.*1047A>G		non_coding_transcript_exon	Exon 21 of 21	ENSP00000430114.1	E5RGW5
IKBKB	ENST00000523517.5	TSL:1	n.*1047A>G		3_prime_UTR	Exon 21 of 21	ENSP00000430114.1	E5RGW5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251480

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.067

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.67

M_CAP

Benign

0.057

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.6

PhyloP100

4.9

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.18

REVEL

Benign

0.16

Sift

Benign

0.48

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.19

MutPred

0.16

Gain of helix (P = 0.0325)

MVP

0.85

MPC

0.46

ClinPred

0.22

GERP RS

5.3

Varity_R

0.15

gMVP

0.19

Mutation Taster

=71/29

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over