rs2272736

Positions:

• chr8-42319645-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong 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. 15/22 in silico tools predict a benign outcome for this variant. 3/3 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, multiple submitters, no conflicts B:2
• 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 -19 ACMG points.

• 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=0.0016427338).
• 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_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
IKBKB	NM_001556.3	c.1577G>A	p.Arg526Gln	missense_variant, splice_region_variant	15/22	ENST00000520810.6	NP_001547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IKBKB	ENST00000520810.6	c.1577G>A	p.Arg526Gln	missense_variant, splice_region_variant	15/22	1	NM_001556.3	ENSP00000430684	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Severe combined immunodeficiency due to IKK2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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
LIST_S2	Benign	0.84	.;T;T;T
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;