chr8-42283031-G-T

Variant names:

• chr8-42283031-G-T
• rs5029748
• NM_001556.3:c.106-5603G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001556.3(IKBKB):​c.106-5603G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,150 control chromosomes in the GnomAD database, including 5,196 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (5196 hom., cov: 32)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.56
• Publications: 26 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001556.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	NM_001556.3	MANE Select	c.106-5603G>T		intron	N/A	NP_001547.1
	IKBKB	NM_001242778.2		c.24-7125G>T		intron	N/A	NP_001229707.1
	IKBKB	NM_001190720.3		c.-87-5603G>T		intron	N/A	NP_001177649.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.106-5603G>T		intron	N/A	ENSP00000430684.1
	IKBKB	ENST00000519735.5	TSL:1	n.276-5603G>T		intron	N/A
	IKBKB	ENST00000523517.5	TSL:1	n.106-5603G>T		intron	N/A	ENSP00000430114.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34202 AN: 152030 Hom.: 5188 Cov.: 32

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.238

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.225 AC: 34221 AN: 152150 Hom.: 5196 Cov.: 32 AF XY: 0.230 AC XY: 17075 AN XY: 74398

African (AFR) AF: 0.0573 AC: 2379 AN: 41548

American (AMR) AF: 0.392 AC: 5981 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1050 AN: 3468

East Asian (EAS) AF: 0.540 AC: 2793 AN: 5168

South Asian (SAS) AF: 0.400 AC: 1933 AN: 4830

European-Finnish (FIN) AF: 0.183 AC: 1936 AN: 10570

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17430 AN: 67980

Other (OTH) AF: 0.237 AC: 500 AN: 2108

Alfa AF: 0.263 Hom.: 6346

Bravo AF: 0.237

Asia WGS AF: 0.391 AC: 1355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.61
PhyloP100		3.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs5029748; hg19: chr8-42140549;