Genetic Variant IKBKB:p.Arg536Trp (chr8-42320762-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -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 (★).

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR 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

GnomAD3 exomes

AF:

0.00218

AC:

543

AN:

249470

Hom.:

AF XY:

0.00225

AC XY:

304

AN XY:

134912

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0200

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000763

GnomAD4 genome

AF:

0.00203

AC:

309

AN:

152336

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

239

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0259

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000223

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over