1-206474470-C-G

Variant names:

• chr1-206474470-C-G
• rs554685342
• NM_014002.4:c.227C>G

Variant summary

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

The NM_014002.4(IKBKE):​c.227C>G​(p.Thr76Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T76M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IKBKE NM_014002.4 missense, splice_region
• Scores: Splicing: ADA: 0.5277
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014002.4. 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.227C>G	p.Thr76Arg	missense splice_region	Exon 4 of 22	NP_054721.1	Q14164-1
	IKBKE	NM_001193322.2		c.227C>G	p.Thr76Arg	missense splice_region	Exon 4 of 21	NP_001180251.1	A0A075B7B4
	IKBKE	NM_001193321.2		c.-29C>G		splice_region	Exon 3 of 21	NP_001180250.1	Q14164-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKE	ENST00000581977.7	TSL:1 MANE Select	c.227C>G	p.Thr76Arg	missense splice_region	Exon 4 of 22	ENSP00000464030.1	Q14164-1
	IKBKE	ENST00000578328.6	TSL:1	c.227C>G	p.Thr76Arg	missense splice_region	Exon 4 of 21	ENSP00000473833.1	A0A075B7B4
	IKBKE	ENST00000584998.5	TSL:1	c.-29C>G		splice_region	Exon 3 of 21	ENSP00000462396.1	Q14164-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.072	T
Polyphen		0.99	D
Vest4		0.54
MutPred		0.66		Gain of MoRF binding (P = 0.0157)
MVP		0.78
ClinPred		0.84	D
GERP RS		4.3
Varity_R		0.11
gMVP		0.58
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.53
dbscSNV1_RF	Benign	0.40
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: rs554685342; hg19: chr1-206647813;