8-42316862-G-T

Variant names:

• chr8-42316862-G-T
• rs56230731
• NM_001556.3:c.1083G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001556.3(IKBKB):​c.1083G>T​(p.Leu361Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L361L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKBKB NM_001556.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• severe combined immunodeficiency due to IKK2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• immunodeficiency 15a

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKBKB	NM_001556.3	c.1083G>T	p.Leu361Phe	missense_variant	Exon 11 of 22	ENST00000520810.6	NP_001547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6	c.1083G>T	p.Leu361Phe	missense_variant	Exon 11 of 22	1	NM_001556.3	ENSP00000430684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M
PhyloP100		4.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N;N;.;N;.
REVEL	Benign	0.25
Sift	Benign	0.038	D;D;.;D;.
Sift4G	Benign	0.12	T;T;T;T;.
Polyphen		1.0	D;.;.;D;D
Vest4		0.79
MutPred		0.36		Loss of disorder (P = 0.0841);.;Loss of disorder (P = 0.0841);.;Loss of disorder (P = 0.0841);
MVP		0.78
MPC		1.3
ClinPred		0.87	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.66
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs56230731; hg19: chr8-42174380;