NM_014002.4:c.2138C>T

Variant names:

• chr1-206496132-C-T
• rs3748022
• NM_014002.4:c.2138C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014002.4(IKBKE):​c.2138C>T​(p.Pro713Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,610,104 control chromosomes in the GnomAD database, including 36,569 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2877 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33692 hom.)
• Consequence: IKBKE NM_014002.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• 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]

IKBKE-AS1 (HGNC:32061): (IKBKE antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047554076).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

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.2138C>T	p.Pro713Leu	missense	Exon 22 of 22	NP_054721.1
	IKBKE	NM_001193321.2		c.1883C>T	p.Pro628Leu	missense	Exon 21 of 21	NP_001180250.1
	IKBKE	NM_001193322.2		c.*51C>T		3_prime_UTR	Exon 21 of 21	NP_001180251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IKBKE	ENST00000581977.7	TSL:1 MANE Select	c.2138C>T	p.Pro713Leu	missense	Exon 22 of 22	ENSP00000464030.1
	IKBKE	ENST00000584998.5	TSL:1	c.1883C>T	p.Pro628Leu	missense	Exon 21 of 21	ENSP00000462396.1
	IKBKE	ENST00000578328.6	TSL:1	c.*51C>T		3_prime_UTR	Exon 21 of 21	ENSP00000473833.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26174 AN: 151970 Hom.: 2880 Cov.: 32

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.206

GnomAD2 exomes AF: 0.199 AC: 50019 AN: 250932 AF XY: 0.197

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.216

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.209 AC: 304607 AN: 1458016 Hom.: 33692 Cov.: 30 AF XY: 0.206 AC XY: 149280 AN XY: 725496

African (AFR) AF: 0.0364 AC: 1217 AN: 33458

American (AMR) AF: 0.272 AC: 12170 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3723 AN: 26100

East Asian (EAS) AF: 0.190 AC: 7523 AN: 39662

South Asian (SAS) AF: 0.0888 AC: 7656 AN: 86170

European-Finnish (FIN) AF: 0.255 AC: 13596 AN: 53398

Middle Eastern (MID) AF: 0.202 AC: 1163 AN: 5748

European-Non Finnish (NFE) AF: 0.222 AC: 245559 AN: 1108534

Other (OTH) AF: 0.199 AC: 12000 AN: 60270

GnomAD4 genome AF: 0.172 AC: 26170 AN: 152088 Hom.: 2877 Cov.: 32 AF XY: 0.175 AC XY: 13023 AN XY: 74344

African (AFR) AF: 0.0428 AC: 1778 AN: 41518

American (AMR) AF: 0.243 AC: 3707 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 546 AN: 3470

East Asian (EAS) AF: 0.200 AC: 1031 AN: 5160

South Asian (SAS) AF: 0.0924 AC: 446 AN: 4826

European-Finnish (FIN) AF: 0.268 AC: 2831 AN: 10564

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15124 AN: 67966

Other (OTH) AF: 0.204 AC: 431 AN: 2110

Alfa AF: 0.203 Hom.: 11822

Bravo AF: 0.169

TwinsUK AF: 0.230 AC: 851

ALSPAC AF: 0.232 AC: 896

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.218 AC: 1876

ExAC AF: 0.193 AC: 23436

Asia WGS AF: 0.118 AC: 410 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.216

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.47	T
Polyphen		0.030	B
Vest4		0.097
ClinPred		0.0080	T
GERP RS		3.5
Varity_R		0.050
gMVP		0.075
Mutation Taster		=100/0	polymorphism (auto)

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: rs3748022; hg19: chr1-206669465; COSMIC: COSV65622766;