chr8-42318647-C-T

Position:

chr8-42318647-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BS1_Supporting

The NM_001556.3(IKBKB):c.1336C>T(p.Arg446Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,613,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

IKBKB
NM_001556.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94

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:

IKBKB (HGNC:):

IKBKB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000698 (102/1461092) while in subpopulation NFE AF= 0.0000846 (94/1111442). AF 95% confidence interval is 0.0000705. There are 0 homozygotes in gnomad4_exome. There are 51 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKB	NM_001556.3 linkuse as main transcript	c.1336C>T	p.Arg446Trp	missense_variant	13/22	ENST00000520810.6	NP_001547.1	O14920-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6 linkuse as main transcript	c.1336C>T	p.Arg446Trp	missense_variant	13/22	1	NM_001556.3	ENSP00000430684.1		O14920-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251282

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461092

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

726776

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000846

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to IKK2 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 446 of the IKBKB protein (p.Arg446Trp). This variant is present in population databases (rs202136671, gnomAD 0.01%). This missense change has been observed in individual(s) with common variable immunodeficiency (CVID) (PMID: 26122175). ClinVar contains an entry for this variant (Variation ID: 577092). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IKBKB protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

T;.;T;.;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.48

T;T;T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.4

L;.;.;.;L

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.1

D;D;.;D;.

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

D;D;.;D;.

Sift4G

Uncertain

0.0070

D;D;D;D;.

Polyphen

1.0

D;.;.;D;D

Vest4

0.69

MutPred

0.50

Loss of disorder (P = 0.0255);.;Loss of disorder (P = 0.0255);.;Loss of disorder (P = 0.0255);

MVP

0.74

MPC

1.1

ClinPred

0.66

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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