rs2272736

chr8-42319645-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_001556.3(IKBKB):c.1577G>A(p.Arg526Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0038 in 1,586,780 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (292 hom.)
• Consequence: IKBKB NM_001556.3 missense, splice_region
• Scores: Splicing: ADA: 0.7745
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.80

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 Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, IKBKB
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016427338).
• BP6: Variant 8-42319645-G-A is Benign according to our data. Variant chr8-42319645-G-A is described in ClinVar as [Benign]. Clinvar id is 474791.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKBKB	NM_001556.3	c.1577G>A	p.Arg526Gln	missense_variant, splice_region_variant	15/22	ENST00000520810.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKBKB	ENST00000520810.6	c.1577G>A	p.Arg526Gln	missense_variant, splice_region_variant	15/22	1	NM_001556.3	P1

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152040 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00897 AC: 2040 AN: 227334 Hom.: 113 AF XY: 0.00862 AC XY: 1062 AN XY: 123220

Gnomad AFR exome AF: 0.000949

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.00295

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00494

GnomAD4 exome AF: 0.00372 AC: 5343 AN: 1434622 Hom.: 292 Cov.: 31 AF XY: 0.00367 AC XY: 2615 AN XY: 712498

Gnomad4 AFR exome AF: 0.000537

Gnomad4 AMR exome AF: 0.000189

Gnomad4 ASJ exome AF: 0.000201

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.00330

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000508

Gnomad4 OTH exome AF: 0.00583

GnomAD4 genome AF: 0.00451 AC: 686 AN: 152158 Hom.: 23 Cov.: 32 AF XY: 0.00526 AC XY: 391 AN XY: 74386

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00445 Hom.: 72

Bravo AF: 0.00549

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00888 AC: 1078

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency due to IKK2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.;T
Eigen	Benign	-0.0025
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L;.;.;L
MutationTaster	Benign	0.000061	P;P;P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.11	N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.46	T;T;T;.
Sift4G	Benign	0.84	T;T;T;.
Polyphen		0.064	B;.;B;B
Vest4		0.072
MVP		0.81
MPC		0.50
ClinPred		0.017	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.48
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: rs2272736; hg19: chr8-42177163; COSMIC: COSV60596127; COSMIC: COSV60596127;