8-42271987-A-G

Variant names:

• chr8-42271987-A-G
• rs3747811
• NM_001556.3:c.-18-96A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_001556.3(IKBKB):​c.-18-96A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,260,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00076 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: IKBKB NM_001556.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 23 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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• immunodeficiency 15a

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000755 (115/152220) while in subpopulation AFR AF = 0.00265 (110/41566). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	NM_001556.3	MANE Select	c.-18-96A>G		intron	N/A	NP_001547.1	O14920-1
	IKBKB	NM_001242778.2		c.-100-96A>G		intron	N/A	NP_001229707.1	O14920-4
	IKBKB	NM_001190720.3		c.-88+518A>G		intron	N/A	NP_001177649.2	A0A499FJS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.-18-96A>G		intron	N/A	ENSP00000430684.1	O14920-1
	IKBKB	ENST00000519735.5	TSL:1	n.153-96A>G		intron	N/A
	IKBKB	ENST00000957021.1		c.-18-96A>G		intron	N/A	ENSP00000627080.1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.0000659 AC: 73 AN: 1107930 Hom.: 0 Cov.: 14 AF XY: 0.0000668 AC XY: 37 AN XY: 553496

African (AFR) AF: 0.00256 AC: 63 AN: 24594

American (AMR) AF: 0.00 AC: 0 AN: 26870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18388

East Asian (EAS) AF: 0.00 AC: 0 AN: 37418

South Asian (SAS) AF: 0.00 AC: 0 AN: 63578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3322

European-Non Finnish (NFE) AF: 0.00000716 AC: 6 AN: 838236

Other (OTH) AF: 0.0000843 AC: 4 AN: 47424

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000712 AC XY: 53 AN XY: 74408

African (AFR) AF: 0.00265 AC: 110 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67992

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00 Hom.: 1051

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.067
DANN	Benign	0.58
PhyloP100		-1.3
PromoterAI		0.043	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3747811;

hg19: chr8-42129505;