8-42322134-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001556.3(IKBKB):c.1819G>C(p.Val607Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. V607M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKBKB NM_001556.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.88

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, IKBKB
• BP4: Computational evidence support a benign effect (MetaRNN=0.11964014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKB	NM_001556.3	c.1819G>C	p.Val607Leu	missense_variant	18/22	ENST00000520810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKB	ENST00000520810.6	c.1819G>C	p.Val607Leu	missense_variant	18/22	1	NM_001556.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IKBKB-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2022

The IKBKB c.1819G>C variant is predicted to result in the amino acid substitution p.Val607Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Severe combined immunodeficiency due to IKK2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;.;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;N
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.51	N;N;N;.
REVEL	Benign	0.031
Sift	Benign	0.24	T;T;T;.
Sift4G	Benign	0.13	T;T;T;.
Polyphen		0.0	B;.;B;B
Vest4		0.20
MutPred		0.19		Loss of methylation at K604 (P = 0.0787);.;.;Loss of methylation at K604 (P = 0.0787);
MVP		0.37
MPC		0.42
ClinPred		0.32	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.098

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

Other links and lift over

dbSNP: rs764627236; hg19: chr8-42179652;