dbSNP rs367889547: NFKB2:p.Gly784Arg (chr10-102401801-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_001322934.2(NFKB2):c.2350G>A(p.Gly784Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

NFKB2
NM_001322934.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.21

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: 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:

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=0.033337206).

BP6

Variant 10-102401801-G-A is Benign according to our data. Variant chr10-102401801-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 576587.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00021 (32/152330) while in subpopulation AFR AF = 0.000746 (31/41572). AF 95% confidence interval is 0.000539. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 32 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	UniProt
NFKB2	NM_001322934.2	MANE Select	c.2350G>A	p.Gly784Arg	missense	Exon 21 of 23	NP_001309863.1	Q00653-1
NFKB2	NM_001077494.3		c.2350G>A	p.Gly784Arg	missense	Exon 21 of 23	NP_001070962.1	Q00653-1
NFKB2	NM_001261403.3		c.2350G>A	p.Gly784Arg	missense	Exon 20 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.2350G>A	p.Gly784Arg	missense	Exon 21 of 23	ENSP00000499294.1	Q00653-1
NFKB2	ENST00000369966.8	TSL:1	c.2350G>A	p.Gly784Arg	missense	Exon 21 of 23	ENSP00000358983.3	Q00653-1
NFKB2	ENST00000189444.11	TSL:1	c.2350G>A	p.Gly784Arg	missense	Exon 21 of 23	ENSP00000189444.6	Q00653-4

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000523

AC:

AN:

248550

AF XY:

0.0000667

show subpopulations

Gnomad AFR exome

AF:

0.000649

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461412

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.0000351

AC:

AN:

1111864

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000210

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000428

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.000254

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000744

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency, common variable, 10 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.33

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

M_CAP

Benign

0.059

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.41

PhyloP100

3.2

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.57

REVEL

Benign

0.14

Sift

Benign

0.42

Sift4G

Benign

0.52

Polyphen

0.031

Vest4

0.37

MutPred

0.35

Loss of catalytic residue at G784 (P = 0.0811)

MVP

0.57

MPC

0.74

ClinPred

0.036

GERP RS

2.9

Varity_R

0.083

gMVP

0.75

Mutation Taster

=73/27

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over