8-42329636-A-G

Variant names:

• chr8-42329636-A-G
• rs6474388
• NM_001556.3:c.2205+422A>G

Variant summary

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

The NM_001556.3(IKBKB):​c.2205+422A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.893 in 984,660 control chromosomes in the GnomAD database, including 400,789 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 0.76 (48261 hom., cov: 32)
  • Exomes 𝑓: 0.92 (352528 hom.)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.979
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.922 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.2205+422A>G		intron	N/A	NP_001547.1
	IKBKB	NM_001242778.2		c.2028+422A>G		intron	N/A	NP_001229707.1
	IKBKB	NM_001190720.3		c.2013+422A>G		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.2205+422A>G		intron	N/A	ENSP00000430684.1
	IKBKB	ENST00000523517.5	TSL:1	n.*1024+422A>G		intron	N/A	ENSP00000430114.1
	IKBKB	ENST00000523599.2	TSL:2	n.1508A>G		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115932 AN: 152056 Hom.: 48243 Cov.: 32

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.945

Gnomad AMR AF: 0.886

Gnomad ASJ AF: 0.936

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.804

GnomAD4 exome AF: 0.916 AC: 762942 AN: 832486 Hom.: 352528 Cov.: 25 AF XY: 0.917 AC XY: 352506 AN XY: 384442

African (AFR) AF: 0.353 AC: 5569 AN: 15756

American (AMR) AF: 0.916 AC: 901 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.935 AC: 4810 AN: 5144

East Asian (EAS) AF: 0.859 AC: 3115 AN: 3626

South Asian (SAS) AF: 0.779 AC: 12814 AN: 16440

European-Finnish (FIN) AF: 0.833 AC: 230 AN: 276

Middle Eastern (MID) AF: 0.880 AC: 1425 AN: 1620

European-Non Finnish (NFE) AF: 0.932 AC: 709896 AN: 761362

Other (OTH) AF: 0.887 AC: 24182 AN: 27278

GnomAD4 genome AF: 0.762 AC: 115978 AN: 152174 Hom.: 48261 Cov.: 32 AF XY: 0.760 AC XY: 56539 AN XY: 74380

African (AFR) AF: 0.395 AC: 16383 AN: 41470

American (AMR) AF: 0.886 AC: 13555 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.936 AC: 3249 AN: 3470

East Asian (EAS) AF: 0.853 AC: 4420 AN: 5180

South Asian (SAS) AF: 0.778 AC: 3758 AN: 4828

European-Finnish (FIN) AF: 0.818 AC: 8665 AN: 10588

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.928 AC: 63134 AN: 68018

Other (OTH) AF: 0.803 AC: 1696 AN: 2112

Alfa AF: 0.880 Hom.: 77920

Bravo AF: 0.755

Asia WGS AF: 0.730 AC: 2536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.50
DANN	Benign	0.34
PhyloP100		-0.98
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: rs6474388; hg19: chr8-42187154;