1-206474444-T-G

Variant names:

• chr1-206474444-T-G
• rs1539243
• ENST00000584998.5:c.-55T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001193321.2(IKBKE):​c.-55T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKBKE NM_001193321.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 47 publications found

Genes affected

IKBKE (HGNC:14552): (inhibitor of nuclear factor kappa B kinase subunit epsilon) IKBKE is a noncanonical I-kappa-B (see MIM 164008) kinase (IKK) that is essential for regulating antiviral signaling pathways. IKBKE has also been identified as a breast cancer (MIM 114480) oncogene and is amplified and overexpressed in over 30% of breast carcinomas and breast cancer cell lines (Hutti et al., 2009 [PubMed 19481526]).[supplied by OMIM, Oct 2009]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193321.2. 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
	IKBKE	NM_014002.4	MANE Select	c.201T>G	p.Ile67Met	missense	Exon 4 of 22	NP_054721.1	Q14164-1
	IKBKE	NM_001193321.2		c.-55T>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 21	NP_001180250.1	Q14164-2
	IKBKE	NM_001193322.2		c.201T>G	p.Ile67Met	missense	Exon 4 of 21	NP_001180251.1	A0A075B7B4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKE	ENST00000584998.5	TSL:1	c.-55T>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 21	ENSP00000462396.1	Q14164-2
	IKBKE	ENST00000581977.7	TSL:1 MANE Select	c.201T>G	p.Ile67Met	missense	Exon 4 of 22	ENSP00000464030.1	Q14164-1
	IKBKE	ENST00000578328.6	TSL:1	c.201T>G	p.Ile67Met	missense	Exon 4 of 21	ENSP00000473833.1	A0A075B7B4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		-1.0
PrimateAI	Uncertain	0.54	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.84		Gain of MoRF binding (P = 0.0726)
MVP		0.99
ClinPred		0.97	D
GERP RS		1.3
Varity_R		0.14
gMVP		0.61
Mutation Taster		=99/1	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: rs1539243; hg19: chr1-206647787;