chr8-42316559-G-A

Variant names:

• chr8-42316559-G-A
• rs12676482
• NM_001556.3:c.931-151G>A

Variant summary

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

The NM_001556.3(IKBKB):​c.931-151G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0693 in 873,876 control chromosomes in the GnomAD database, including 4,559 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 0.12 (1899 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2660 hom.)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.441
• Publications: 12 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 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.931-151G>A		intron	N/A	NP_001547.1
	IKBKB	NM_001242778.2		c.754-151G>A		intron	N/A	NP_001229707.1
	IKBKB	NM_001190720.3		c.739-151G>A		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.931-151G>A		intron	N/A	ENSP00000430684.1
	IKBKB	ENST00000523517.5	TSL:1	n.931-151G>A		intron	N/A	ENSP00000430114.1
	IKBKB	ENST00000520835.7	TSL:2	c.739-151G>A		intron	N/A	ENSP00000430868.2

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17689 AN: 152088 Hom.: 1897 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.0594 AC: 42882 AN: 721670 Hom.: 2660 AF XY: 0.0627 AC XY: 23001 AN XY: 366914

African (AFR) AF: 0.280 AC: 4900 AN: 17506

American (AMR) AF: 0.0461 AC: 922 AN: 20016

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 327 AN: 15526

East Asian (EAS) AF: 0.150 AC: 4876 AN: 32450

South Asian (SAS) AF: 0.181 AC: 9309 AN: 51308

European-Finnish (FIN) AF: 0.0939 AC: 3533 AN: 37612

Middle Eastern (MID) AF: 0.0622 AC: 159 AN: 2556

European-Non Finnish (NFE) AF: 0.0321 AC: 16385 AN: 509986

Other (OTH) AF: 0.0712 AC: 2471 AN: 34710

GnomAD4 genome AF: 0.116 AC: 17713 AN: 152206 Hom.: 1899 Cov.: 32 AF XY: 0.122 AC XY: 9063 AN XY: 74404

African (AFR) AF: 0.274 AC: 11369 AN: 41508

American (AMR) AF: 0.0563 AC: 861 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3470

East Asian (EAS) AF: 0.140 AC: 723 AN: 5176

South Asian (SAS) AF: 0.198 AC: 954 AN: 4820

European-Finnish (FIN) AF: 0.115 AC: 1223 AN: 10592

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0328 AC: 2232 AN: 68028

Other (OTH) AF: 0.113 AC: 238 AN: 2114

Alfa AF: 0.0566 Hom.: 424

Bravo AF: 0.115

Asia WGS AF: 0.232 AC: 807 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.65
PhyloP100		-0.44
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: rs12676482; hg19: chr8-42174077;