NM_004556.3:c.164T>C

Variant names:

• chr6-44265183-A-G
• rs2233434
• NM_004556.3:c.164T>C

Variant summary

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

The NM_004556.3(NFKBIE):​c.164T>C​(p.Val55Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 1,551,674 control chromosomes in the GnomAD database, including 2,343 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.052 (276 hom., cov: 33)
  • Exomes 𝑓: 0.046 (2067 hom.)
• Consequence: NFKBIE NM_004556.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57
• Publications: 54 publications found

Genes affected

NFKBIE (HGNC:7799): (NFKB inhibitor epsilon) The protein encoded by this gene binds to components of NF-kappa-B, trapping the complex in the cytoplasm and preventing it from activating genes in the nucleus. Phosphorylation of the encoded protein targets it for destruction by the ubiquitin pathway, which activates NF-kappa-B by making it available to translocate to the nucleus. [provided by RefSeq, Sep 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014121234).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004556.3. 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
	NFKBIE	NM_004556.3	MANE Select	c.164T>C	p.Val55Ala	missense	Exon 1 of 6	NP_004547.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIE	ENST00000619360.6	TSL:1 MANE Select	c.164T>C	p.Val55Ala	missense	Exon 1 of 6	ENSP00000480216.1
	NFKBIE	ENST00000275015.9	TSL:1	c.581T>C	p.Val194Ala	missense	Exon 1 of 6	ENSP00000275015.3
	NFKBIE	ENST00000477930.2	TSL:3	n.164T>C		non_coding_transcript_exon	Exon 1 of 3	ENSP00000454778.2

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 7900 AN: 152130 Hom.: 276 Cov.: 33

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0798

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0421

GnomAD2 exomes AF: 0.0493 AC: 7662 AN: 155550 AF XY: 0.0464

Gnomad AFR exome AF: 0.0637

Gnomad AMR exome AF: 0.0404

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.163

Gnomad FIN exome AF: 0.0711

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0411

GnomAD4 exome AF: 0.0460 AC: 64350 AN: 1399426 Hom.: 2067 Cov.: 33 AF XY: 0.0451 AC XY: 31153 AN XY: 690260

African (AFR) AF: 0.0611 AC: 1932 AN: 31620

American (AMR) AF: 0.0417 AC: 1488 AN: 35712

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 472 AN: 25168

East Asian (EAS) AF: 0.192 AC: 6879 AN: 35760

South Asian (SAS) AF: 0.0211 AC: 1671 AN: 79226

European-Finnish (FIN) AF: 0.0677 AC: 3336 AN: 49260

Middle Eastern (MID) AF: 0.0159 AC: 90 AN: 5676

European-Non Finnish (NFE) AF: 0.0423 AC: 45609 AN: 1078992

Other (OTH) AF: 0.0495 AC: 2873 AN: 58012

GnomAD4 genome AF: 0.0520 AC: 7911 AN: 152248 Hom.: 276 Cov.: 33 AF XY: 0.0531 AC XY: 3952 AN XY: 74444

African (AFR) AF: 0.0590 AC: 2450 AN: 41558

American (AMR) AF: 0.0457 AC: 699 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.172 AC: 889 AN: 5166

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4826

European-Finnish (FIN) AF: 0.0798 AC: 846 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0405 AC: 2755 AN: 68002

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0452 Hom.: 814

Bravo AF: 0.0512

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0387 AC: 149

ESP6500AA AF: 0.0582 AC: 240

ESP6500EA AF: 0.0336 AC: 274

ExAC AF: 0.0198 AC: 1768

Asia WGS AF: 0.0910 AC: 314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.3	N
PhyloP100		1.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.048
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.92
ClinPred		0.0012	T
GERP RS		2.7
PromoterAI		0.034	Neutral
Varity_R		0.026
gMVP		0.14
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: rs2233434; hg19: chr6-44232920; COSMIC: COSV51487967;