rs2233434

Positions:

• chr6-44265183-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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]

POLR1C (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIE	NM_004556.3	c.164T>C	p.Val55Ala	missense_variant	1/6	ENST00000619360.6
POLR1C	NM_001318876.2	c.946-176707A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIE	ENST00000619360.6	c.164T>C	p.Val55Ala	missense_variant	1/6	1	NM_004556.3	P1
NFKBIE	ENST00000275015.9	c.581T>C	p.Val194Ala	missense_variant	1/6	1
NFKBIE	ENST00000477930.2	c.164T>C	p.Val55Ala	missense_variant, NMD_transcript_variant	1/3	3

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

GnomAD3 exomes AF: 0.0493 AC: 7662 AN: 155550 Hom.: 307 AF XY: 0.0464 AC XY: 3809 AN XY: 82142

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 SAS exome AF: 0.0196

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

Gnomad4 AFR exome AF: 0.0611

Gnomad4 AMR exome AF: 0.0417

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.0211

Gnomad4 FIN exome AF: 0.0677

Gnomad4 NFE exome AF: 0.0423

Gnomad4 OTH exome AF: 0.0495

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

Gnomad4 AFR AF: 0.0590

Gnomad4 AMR AF: 0.0457

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0798

Gnomad4 NFE AF: 0.0405

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0422 Hom.: 338

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 v4.3

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;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.060	T;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.3	.;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.48	.;N
REVEL	Benign	0.048
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.022
MPC		0.92
ClinPred		0.0012	T
GERP RS		2.7
Varity_R		0.026
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs2233434; hg19: chr6-44232920; COSMIC: COSV51487967;