8-42320762-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001556.3(IKBKB):c.1606C>T(p.Arg536Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000972 in 1,612,576 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts 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. R536G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 24 hom. )

Consequence

IKBKB
NM_001556.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.57

Publications

5 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004968941).

BP6

Variant 8-42320762-C-T is Benign according to our data. Variant chr8-42320762-C-T is described in ClinVar as Benign. ClinVar VariationId is 541648.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00203 (309/152336) while in subpopulation NFE AF = 0.000397 (27/68032). AF 95% confidence interval is 0.00028. There are 3 homozygotes in GnomAd4. There are 239 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKB	NM_001556.3 link	c.1606C>T	p.Arg536Trp	missense_variant	Exon 16 of 22	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.1606C>T	p.Arg536Trp	missense_variant	Exon 16 of 22	1	NM_001556.3	ENSP00000430684.1		O14920-1

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0259

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00218

AC:

543

AN:

249470

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000275

Gnomad FIN exome

AF:

0.0223

Gnomad NFE exome

AF:

0.000355

Gnomad OTH exome

AF:

0.00230

GnomAD4 exome

AF:

0.000862

AC:

1259

AN:

1460240

Hom.:

Cov.:

AF XY:

0.000871

AC XY:

633

AN XY:

726484

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.000152

AC:

AN:

39520

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.0200

AC:

1067

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000121

AC:

135

AN:

1111164

Other (OTH)

AF:

0.000763

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00203

AC:

309

AN:

152336

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

239

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0259

AC:

275

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000335

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00185

AC:

225

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to IKK2 deficiency

Benign:1

Jan 10, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;.;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

.;D;D;D

MetaRNN

Benign

0.0050

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.1

L;.;.;L

PhyloP100

2.6

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.8

D;D;D;.

REVEL

Benign

0.11

Sift

Uncertain

0.0040

D;D;D;.

Sift4G

Uncertain

0.0050

D;D;D;.

Polyphen

0.99

D;.;D;D

Vest4

0.50

MVP

0.30

MPC

0.74

ClinPred

0.060

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.61

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over