Genetic Variant NFKB2:p.Ala421Glu (chr10-102399432-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001322934.2(NFKB2):c.1262C>A(p.Ala421Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A421S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NFKB2
NM_001322934.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.242

Publications

1 publications found

Variant links:

Genes affected

NFKB2 (HGNC:7795): (nuclear factor kappa B subunit 2) This gene encodes a subunit of the transcription factor complex nuclear factor-kappa-B (NFkB). The NFkB complex is expressed in numerous cell types and functions as a central activator of genes involved in inflammation and immune function. The protein encoded by this gene can function as both a transcriptional activator or repressor depending on its dimerization partner. The p100 full-length protein is co-translationally processed into a p52 active form. Chromosomal rearrangements and translocations of this locus have been observed in B cell lymphomas, some of which may result in the formation of fusion proteins. There is a pseudogene for this gene on chromosome 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

NFKB2 Gene-Disease associations (from GenCC):

immunodeficiency, common variable, 10
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
deficiency in anterior pituitary function - variable immunodeficiency syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NFKB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03799981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB2	NM_001322934.2 link	c.1262C>A	p.Ala421Glu	missense_variant	Exon 13 of 23	ENST00000661543.1	NP_001309863.1	Q00653-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1 link	c.1262C>A	p.Ala421Glu	missense_variant	Exon 13 of 23		NM_001322934.2	ENSP00000499294.1		Q00653-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1367724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672484

African (AFR)

AF:

0.00

AC:

AN:

29548

American (AMR)

AF:

0.00

AC:

AN:

31320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23468

East Asian (EAS)

AF:

0.00

AC:

AN:

34556

South Asian (SAS)

AF:

0.00

AC:

AN:

76634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4980

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1063626

Other (OTH)

AF:

0.00

AC:

AN:

56328

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.74

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.072

.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.51

T;T;.

M_CAP

Benign

0.0092

MetaRNN

Benign

0.038

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

-0.24

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.63

N;N;N

REVEL

Benign

0.018

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.12

MutPred

0.30

Gain of solvent accessibility (P = 0.0023);Gain of solvent accessibility (P = 0.0023);Gain of solvent accessibility (P = 0.0023);

MVP

0.12

MPC

0.71

ClinPred

0.062

GERP RS

1.9

Varity_R

0.025

gMVP

0.35

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over