Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001322934.2(NFKB2):c.1821A>G(p.Ala607Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,014 control chromosomes in the GnomAD database, including 803,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A607A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.99 ( 74597 hom., cov: 32)

Exomes 𝑓: 1.0 ( 729155 hom. )

Consequence

NFKB2
NM_001322934.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.85

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 10-102400677-A-G is Benign according to our data. Variant chr10-102400677-A-G is described in ClinVar as Benign. ClinVar VariationId is 403234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.85 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.1821A>G	p.Ala607Ala	synonymous	Exon 17 of 23	NP_001309863.1
NFKB2	NM_001077494.3		c.1821A>G	p.Ala607Ala	synonymous	Exon 17 of 23	NP_001070962.1
NFKB2	NM_001261403.3		c.1821A>G	p.Ala607Ala	synonymous	Exon 16 of 22	NP_001248332.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NFKB2	ENST00000661543.1	MANE Select	c.1821A>G	p.Ala607Ala	synonymous	Exon 17 of 23	ENSP00000499294.1
NFKB2	ENST00000369966.8	TSL:1	c.1821A>G	p.Ala607Ala	synonymous	Exon 17 of 23	ENSP00000358983.3
NFKB2	ENST00000189444.11	TSL:1	c.1821A>G	p.Ala607Ala	synonymous	Exon 17 of 23	ENSP00000189444.6

Frequencies

GnomAD3 genomes

AF:

0.990

AC:

150578

AN:

152140

Hom.:

74538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.965

Gnomad AMI

AF:

0.997

Gnomad AMR

AF:

0.995

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.994

GnomAD2 exomes

AF:

0.997

AC:

248202

AN:

248898

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.962

Gnomad AMR exome

AF:

0.998

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.999

GnomAD4 exome

AF:

0.999

AC:

1460002

AN:

1461756

Hom.:

729155

Cov.:

AF XY:

0.999

AC XY:

726377

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.961

AC:

32181

AN:

33478

American (AMR)

AF:

0.998

AC:

44596

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26121

AN:

26126

East Asian (EAS)

AF:

1.00

AC:

39700

AN:

39700

South Asian (SAS)

AF:

1.00

AC:

86218

AN:

86226

European-Finnish (FIN)

AF:

1.00

AC:

53412

AN:

53414

Middle Eastern (MID)

AF:

0.998

AC:

5754

AN:

5766

European-Non Finnish (NFE)

AF:

1.00

AC:

1111802

AN:

1111960

Other (OTH)

AF:

0.997

AC:

60218

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21670

43340

65010

86680

108350

<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:

0.990

AC:

150696

AN:

152258

Hom.:

74597

Cov.:

AF XY:

0.990

AC XY:

73698

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.965

AC:

40064

AN:

41516

American (AMR)

AF:

0.995

AC:

15230

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3471

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5176

AN:

5176

South Asian (SAS)

AF:

1.00

AC:

4830

AN:

4830

European-Finnish (FIN)

AF:

1.00

AC:

10624

AN:

10624

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68001

AN:

68014

Other (OTH)

AF:

0.994

AC:

2099

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.996

Hom.:

30589

Bravo

AF:

0.988

Asia WGS

AF:

0.999

AC:

3474

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Immunodeficiency, common variable, 10 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.069

(source)

DANN

Benign

0.66

PhyloP100

-1.8

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over