8-42322134-G-C

Variant names:

• chr8-42322134-G-C
• rs764627236
• NM_001556.3:c.1819G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001556.3(IKBKB):​c.1819G>C​(p.Val607Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V607M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKBKB NM_001556.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.88
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11964014).

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.1819G>C	p.Val607Leu	missense	Exon 18 of 22	NP_001547.1
	IKBKB	NM_001242778.2		c.1642G>C	p.Val548Leu	missense	Exon 17 of 21	NP_001229707.1
	IKBKB	NM_001190720.3		c.1627G>C	p.Val543Leu	missense	Exon 17 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.1819G>C	p.Val607Leu	missense	Exon 18 of 22	ENSP00000430684.1
	IKBKB	ENST00000523517.5	TSL:1	n.*638G>C		non_coding_transcript_exon	Exon 17 of 21	ENSP00000430114.1
	IKBKB	ENST00000523517.5	TSL:1	n.*638G>C		3_prime_UTR	Exon 17 of 21	ENSP00000430114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IKBKB-related disorder Uncertain:1

Dec 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The IKBKB c.1819G>C variant is predicted to result in the amino acid substitution p.Val607Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Severe combined immunodeficiency due to IKK2 deficiency Uncertain:1

Feb 10, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.031
Sift	Benign	0.24	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.19		Loss of methylation at K604 (P = 0.0787)
MVP		0.37
MPC		0.42
ClinPred		0.32	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.098
Mutation Taster		=81/19	polymorphism

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: rs764627236; hg19: chr8-42179652;