rs886041036

Positions:

• chr8-42318599-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001556.3(IKBKB):​c.1292dup​(p.Gln432ProfsTer62) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKBKB NM_001556.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.97

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-42318599-T-TG is Pathogenic according to our data. Variant chr8-42318599-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 102445.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKB	NM_001556.3	c.1292dup	p.Gln432ProfsTer62	frameshift_variant	13/22	ENST00000520810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKB	ENST00000520810.6	c.1292dup	p.Gln432ProfsTer62	frameshift_variant	13/22	1	NM_001556.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

IKBKB-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The IKBKB c.1292dupG variant is predicted to result in a frameshift and premature protein termination (p.Gln432Profs*62). This variant has been reported in the homozygous state in several individuals with IKBKB-related immune deficiency (Pannicke et al. 2013. PubMed ID: 24369075; Rubin et al. 2018. PubMed ID: 30288645; Cuvelier et al. 2019. PubMed ID: 30391351). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in IKBKB are expected to be pathogenic. This variant is interpreted as pathogenic. -

Severe combined immunodeficiency due to IKK2 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 26, 2013

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs886041036; hg19: chr8-42176117;