chr8-42318599-T-TG

Variant names:

• chr8-42318599-T-TG
• rs886041036
• NM_001556.3:c.1292dupG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001556.3(IKBKB):​c.1292dupG​(p.Gln432ProfsTer62) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKBKB NM_001556.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.97
• Publications: 9 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-42318599-T-TG is Pathogenic according to our data. Variant chr8-42318599-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 102445.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1292dupG	p.Gln432ProfsTer62	frameshift	Exon 13 of 22	NP_001547.1
	IKBKB	NM_001242778.2		c.1115dupG	p.Gln373ProfsTer62	frameshift	Exon 12 of 21	NP_001229707.1
	IKBKB	NM_001190720.3		c.1100dupG	p.Gln368ProfsTer62	frameshift	Exon 12 of 21	NP_001177649.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKB	ENST00000520810.6	TSL:1 MANE Select	c.1292dupG	p.Gln432ProfsTer62	frameshift	Exon 13 of 22	ENSP00000430684.1
	IKBKB	ENST00000523517.5	TSL:1	n.*111dupG		non_coding_transcript_exon	Exon 12 of 21	ENSP00000430114.1
	IKBKB	ENST00000523517.5	TSL:1	n.*111dupG		3_prime_UTR	Exon 12 of 21	ENSP00000430114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	IKBKB-related disorder (1)
1	-	-	Severe combined immunodeficiency due to IKK2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs886041036; hg19: chr8-42176117;