Genetic Variant NFKB2:p.Thr429Pro (chr10-102399455-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001322934.2(NFKB2):c.1285A>C(p.Thr429Pro) 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. T429N) 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: -1.96

Publications

0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07308319).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322934.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFKB2	NM_001322934.2	MANE Select	c.1285A>C	p.Thr429Pro	missense	Exon 13 of 23	NP_001309863.1	Q00653-1
NFKB2	NM_001077494.3		c.1285A>C	p.Thr429Pro	missense	Exon 13 of 23	NP_001070962.1	Q00653-1
NFKB2	NM_001261403.3		c.1285A>C	p.Thr429Pro	missense	Exon 12 of 22	NP_001248332.1	Q00653-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFKB2	ENST00000661543.1	MANE Select	c.1285A>C	p.Thr429Pro	missense	Exon 13 of 23	ENSP00000499294.1	Q00653-1
NFKB2	ENST00000369966.8	TSL:1	c.1285A>C	p.Thr429Pro	missense	Exon 13 of 23	ENSP00000358983.3	Q00653-1
NFKB2	ENST00000189444.11	TSL:1	c.1285A>C	p.Thr429Pro	missense	Exon 13 of 23	ENSP00000189444.6	Q00653-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1360500

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

668208

African (AFR)

AF:

0.00

AC:

AN:

29080

American (AMR)

AF:

0.00

AC:

AN:

31022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22992

East Asian (EAS)

AF:

0.00

AC:

AN:

34098

South Asian (SAS)

AF:

0.00

AC:

AN:

75610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5102

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1060468

Other (OTH)

AF:

0.00

AC:

AN:

56118

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.57

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.078

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.29

M_CAP

Benign

0.0030

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-2.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.63

REVEL

Benign

0.0080

Sift

Benign

0.17

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.21

MutPred

0.26

Gain of loop (P = 3e-04)

MVP

0.26

MPC

0.80

ClinPred

0.087

GERP RS

-6.0

Varity_R

0.094

gMVP

0.22

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over