Genetic Variant NM_001322934.2:c.40G>A (chr10-102396271-G-A) – ACMG Classification: Benign (-20 pts)

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.40G>A(p.Glu14Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000841 in 1,612,586 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00051 ( 3 hom. )

Consequence

NFKB2
NM_001322934.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.74

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006150514).

BP6

Variant 10-102396271-G-A is Benign according to our data. Variant chr10-102396271-G-A is described in ClinVar as Benign. ClinVar VariationId is 474786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00405 (617/152224) while in subpopulation AFR AF = 0.0136 (566/41538). AF 95% confidence interval is 0.0127. There are 4 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 617 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.40G>A	p.Glu14Lys	missense	Exon 3 of 23	NP_001309863.1	Q00653-1
NFKB2	NM_001077494.3		c.40G>A	p.Glu14Lys	missense	Exon 3 of 23	NP_001070962.1	Q00653-1
NFKB2	NM_001261403.3		c.40G>A	p.Glu14Lys	missense	Exon 2 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.40G>A	p.Glu14Lys	missense	Exon 3 of 23	ENSP00000499294.1	Q00653-1
NFKB2	ENST00000369966.8	TSL:1	c.40G>A	p.Glu14Lys	missense	Exon 3 of 23	ENSP00000358983.3	Q00653-1
NFKB2	ENST00000189444.11	TSL:1	c.40G>A	p.Glu14Lys	missense	Exon 3 of 23	ENSP00000189444.6	Q00653-4

Frequencies

GnomAD3 genomes

AF:

0.00403

AC:

613

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00119

AC:

298

AN:

249404

AF XY:

0.000902

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00547

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000506

AC:

739

AN:

1460362

Hom.:

Cov.:

AF XY:

0.000467

AC XY:

339

AN XY:

726134

show subpopulations

African (AFR)

AF:

0.0147

AC:

493

AN:

33450

American (AMR)

AF:

0.000694

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00486

AC:

127

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1110790

Other (OTH)

AF:

0.00101

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00405

AC:

617

AN:

152224

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0136

AC:

566

AN:

41538

American (AMR)

AF:

0.00150

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68008

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

122

152

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:

0.00167

Hom.:

Bravo

AF:

0.00467

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00139

AC:

168

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency, common variable, 10 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.026

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0062

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

4.7

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.62

REVEL

Benign

0.018

Sift

Benign

0.051

Sift4G

Benign

0.12

Polyphen

0.12

Vest4

0.31

MVP

0.52

MPC

1.4

ClinPred

0.024

GERP RS

3.9

Varity_R

0.14

gMVP

0.93

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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