Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001322934.2(NFKB2):c.2167G>A(p.Asp723Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,611,764 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D723D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 2 hom. )

Consequence

NFKB2
NM_001322934.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 3.22

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05064088).

BP6

Variant 10-102401275-G-A is Benign according to our data. Variant chr10-102401275-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 541632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00048 (73/152138) while in subpopulation NFE AF = 0.00101 (69/68020). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 73 AD gene.

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
NFKB2	NM_001322934.2	MANE Select	c.2167G>A	p.Asp723Asn	missense	Exon 19 of 23	NP_001309863.1
NFKB2	NM_001077494.3		c.2167G>A	p.Asp723Asn	missense	Exon 19 of 23	NP_001070962.1
NFKB2	NM_001261403.3		c.2167G>A	p.Asp723Asn	missense	Exon 18 of 22	NP_001248332.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NFKB2	ENST00000661543.1	MANE Select	c.2167G>A	p.Asp723Asn	missense	Exon 19 of 23	ENSP00000499294.1
NFKB2	ENST00000369966.8	TSL:1	c.2167G>A	p.Asp723Asn	missense	Exon 19 of 23	ENSP00000358983.3
NFKB2	ENST00000189444.11	TSL:1	c.2167G>A	p.Asp723Asn	missense	Exon 19 of 23	ENSP00000189444.6

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000436

AC:

108

AN:

247504

AF XY:

0.000417

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000470

Gnomad NFE exome

AF:

0.000845

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000647

AC:

945

AN:

1459626

Hom.:

Cov.:

AF XY:

0.000602

AC XY:

437

AN XY:

725944

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33430

American (AMR)

AF:

0.0000225

AC:

AN:

44488

Ashkenazi Jewish (ASJ)

AF:

0.0000769

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

85966

European-Finnish (FIN)

AF:

0.000920

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000791

AC:

879

AN:

1110814

Other (OTH)

AF:

0.000199

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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:

0.000480

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.000733

Hom.:

Bravo

AF:

0.000363

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000356

AC:

ExAC

AF:

0.000562

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency, common variable, 10 (1)

Inborn genetic diseases (1)

NFKB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

0.067

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.79

M_CAP

Benign

0.041

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.6

PhyloP100

3.2

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.5

REVEL

Benign

0.043

Sift

Benign

0.032

Sift4G

Benign

0.078

Polyphen

0.65

Vest4

0.091

MVP

0.50

MPC

0.60

ClinPred

0.031

GERP RS

4.4

Varity_R

0.074

gMVP

0.35

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over