NM_001322934.2:c.1288C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001322934.2(NFKB2):c.1288C>T(p.Pro430Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,508,150 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P430L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 8 hom. )

Consequence

NFKB2
NM_001322934.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.21

Publications

3 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009656459).

BP6

Variant 10-102399458-C-T is Benign according to our data. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775. Variant chr10-102399458-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 474775.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00121 (184/152358) while in subpopulation NFE AF = 0.00207 (141/68036). AF 95% confidence interval is 0.00179. There are 1 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB2	NM_001322934.2 link	c.1288C>T	p.Pro430Ser	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.1288C>T	p.Pro430Ser	missense_variant	Exon 13 of 23		NM_001322934.2	ENSP00000499294.1		Q00653-1

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

184

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000984

AC:

108

AN:

109778

AF XY:

0.000920

show subpopulations

Gnomad AFR exome

AF:

0.000242

Gnomad AMR exome

AF:

0.000417

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00184

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.000633

GnomAD4 exome

AF:

0.00230

AC:

3116

AN:

1355792

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1445

AN XY:

665190

show subpopulations

African (AFR)

AF:

0.000244

AC:

AN:

28674

American (AMR)

AF:

0.000465

AC:

AN:

30114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22738

East Asian (EAS)

AF:

0.00

AC:

AN:

33768

South Asian (SAS)

AF:

0.0000930

AC:

AN:

75232

European-Finnish (FIN)

AF:

0.00168

AC:

AN:

46388

Middle Eastern (MID)

AF:

0.000192

AC:

AN:

5214

European-Non Finnish (NFE)

AF:

0.00275

AC:

2907

AN:

1057818

Other (OTH)

AF:

0.00183

AC:

102

AN:

55846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

202

404

607

809

1011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00121

AC:

184

AN:

152358

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41582

American (AMR)

AF:

0.000261

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00231

Hom.:

Bravo

AF:

0.00119

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 10

Benign:2

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NFKB2-related disorder

Benign:1

Feb 17, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NFKB2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.0

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.083

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.60

T;T;.

M_CAP

Benign

0.0071

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M;M

PhyloP100

1.2

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.15

N;N;N

REVEL

Benign

0.040

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.68

T;T;T

Polyphen

0.011

.;B;.

Vest4

0.10

MVP

0.28

MPC

0.62

ClinPred

0.015

GERP RS

3.6

Varity_R

0.019

gMVP

0.27

Mutation Taster

=100/0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over