8-42272108-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001556.3(IKBKB):c.8G>T(p.Trp3Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IKBKB NM_001556.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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 2 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=0.36263943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKB	NM_001556.3	c.8G>T	p.Trp3Leu	missense_variant	2/22	ENST00000520810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKB	ENST00000520810.6	c.8G>T	p.Trp3Leu	missense_variant	2/22	1	NM_001556.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2022

The c.8G>T (p.W3L) alteration is located in exon 2 (coding exon 1) of the IKBKB gene. This alteration results from a G to T substitution at nucleotide position 8, causing the tryptophan (W) at amino acid position 3 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Benign	0.97
DEOGEN2	Benign	0.099	T;T;T;T;.
Eigen	Benign	0.025
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.6	L;.;L;.;.
MutationTaster	Benign	0.95	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.51	N;.;.;D;D
REVEL	Benign	0.22
Sift	Benign	0.14	T;.;.;D;D
Sift4G	Benign	0.15	T;T;.;T;D
Polyphen		0.069	B;.;B;.;.
Vest4		0.47
MutPred		0.30		Gain of glycosylation at S2 (P = 0.0392);Gain of glycosylation at S2 (P = 0.0392);Gain of glycosylation at S2 (P = 0.0392);Gain of glycosylation at S2 (P = 0.0392);Gain of glycosylation at S2 (P = 0.0392);
MVP		0.88
MPC		1.8
ClinPred		0.91	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-42129626;