rs115698972

Positions:

chr8-42319409-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 4 hom. )

Consequence

IKBKB
NM_001556.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IKBKB. . Gene score misZ 2.5876 (greater than the threshold 3.09). Trascript score misZ 3.3125 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency 15a, severe combined immunodeficiency due to IKK2 deficiency.

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 [Benign]. Clinvar id is 541644.Status of the report is criteria_provided_single_submitter, 1 stars.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKB	NM_001556.3 linkuse as main transcript	c.1504G>A	p.Glu502Lys	missense_variant	14/22	ENST00000520810.6	NP_001547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6 linkuse as main transcript	c.1504G>A	p.Glu502Lys	missense_variant	14/22	1	NM_001556.3	ENSP00000430684	P1	O14920-1

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

GnomAD3 exomes

AF:

0.000760

AC:

191

AN:

251456

Hom.:

AF XY:

0.000559

AC XY:

AN XY:

135896

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 SAS 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

Gnomad4 AFR exome

AF:

0.0122

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.00311

AC:

474

AN:

152282

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

211

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0109

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000546

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

IKBKB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Severe combined immunodeficiency due to IKK2 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;T;.;T

Eigen

Benign

0.058

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

.;D;D;D;D

MetaRNN

Benign

0.0073

T;T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.3

L;.;.;.;L

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.010

N;N;.;N;.

REVEL

Benign

0.13

Sift

Benign

0.53

T;T;.;T;.

Sift4G

Benign

0.58

T;T;T;T;.

Polyphen

0.067

B;.;.;B;B

Vest4

0.34

MVP

0.75

MPC

0.57

ClinPred

0.012

GERP RS

6.0

Varity_R

0.35

gMVP

0.25

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

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