8-42272114-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BS1_Supporting

The NM_001556.3(IKBKB):c.14C>T(p.Pro5Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IKBKB NM_001556.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, IKBKB
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000684 (10/1461834) while in subpopulation MID AF= 0.000347 (2/5758). AF 95% confidence interval is 0.000061. There are 0 homozygotes in gnomad4_exome. There are 4 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	UniProt
IKBKB	NM_001556.3	c.14C>T	p.Pro5Leu	missense_variant	2/22	ENST00000520810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKB	ENST00000520810.6	c.14C>T	p.Pro5Leu	missense_variant	2/22	1	NM_001556.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251396 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135860

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 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: 0.00000684 AC: 10 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency due to IKK2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the IKBKB protein (p.Pro5Leu). This variant is present in population databases (rs201805807, gnomAD 0.0008%). This variant has not been reported in the literature in individuals affected with IKBKB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1349650). 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	0.22
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;T;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.8	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;.;.;D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;.;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.56
MutPred		0.33		Loss of glycosylation at P5 (P = 0.0163);Loss of glycosylation at P5 (P = 0.0163);Loss of glycosylation at P5 (P = 0.0163);Loss of glycosylation at P5 (P = 0.0163);Loss of glycosylation at P5 (P = 0.0163);
MVP		0.83
MPC		2.3
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.84
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs201805807; hg19: chr8-42129632;