chr8-42330936-A-G

Position:

• chr8-42330936-A-G

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.2228A>G​(p.Gln743Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IKBKB NM_001556.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IKBKB. . Gene score misZ 2.5876 (greater than the threshold 3.09). Trascript score misZ 3.3125 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency 15a, severe combined immunodeficiency due to IKK2 deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10410881).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IKBKB	NM_001556.3	c.2228A>G	p.Gln743Arg	missense_variant	22/22	ENST00000520810.6	NP_001547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6	c.2228A>G	p.Gln743Arg	missense_variant	22/22	1	NM_001556.3	ENSP00000430684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Benign	0.067	T;.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.67	.;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.6	L;.;.;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.18	N;N;N;.
REVEL	Benign	0.16
Sift	Benign	0.48	T;T;T;.
Sift4G	Benign	0.56	T;T;T;.
Polyphen		0.0	B;.;B;B
Vest4		0.19
MutPred		0.16		Gain of helix (P = 0.0325);.;.;Gain of helix (P = 0.0325);
MVP		0.85
MPC		0.46
ClinPred		0.22	T
GERP RS		5.3
Varity_R		0.15
gMVP		0.19

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: rs201869683; hg19: chr8-42188454;