dbSNP rs4919633: NFKB2:p.Pro423Pro (chr10-102399439-A-G) – ACMG Classification: Benign (-21 pts)

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.1269A>G(p.Pro423Pro) 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 1,515,066 control chromosomes in the GnomAD database, including 754,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 74627 hom., cov: 33)

Exomes 𝑓: 1.0 ( 679817 hom. )

Consequence

NFKB2
NM_001322934.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0690

Publications

18 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=-0.83).

BP6

Variant 10-102399439-A-G is Benign according to our data. Variant chr10-102399439-A-G is described in ClinVar as Benign. ClinVar VariationId is 403233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.069 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.1269A>G	p.Pro423Pro	synonymous	Exon 13 of 23	NP_001309863.1
NFKB2	NM_001077494.3		c.1269A>G	p.Pro423Pro	synonymous	Exon 13 of 23	NP_001070962.1
NFKB2	NM_001261403.3		c.1269A>G	p.Pro423Pro	synonymous	Exon 12 of 22	NP_001248332.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NFKB2	ENST00000661543.1	MANE Select	c.1269A>G	p.Pro423Pro	synonymous	Exon 13 of 23	ENSP00000499294.1
NFKB2	ENST00000369966.8	TSL:1	c.1269A>G	p.Pro423Pro	synonymous	Exon 13 of 23	ENSP00000358983.3
NFKB2	ENST00000189444.11	TSL:1	c.1269A>G	p.Pro423Pro	synonymous	Exon 13 of 23	ENSP00000189444.6

Frequencies

GnomAD3 genomes

AF:

0.990

AC:

150636

AN:

152196

Hom.:

74568

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:

0.998

AC:

117165

AN:

117444

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.959

Gnomad AMR exome

AF:

0.997

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:

1361164

AN:

1362752

Hom.:

679817

Cov.:

AF XY:

0.999

AC XY:

668825

AN XY:

669554

show subpopulations

African (AFR)

AF:

0.960

AC:

27996

AN:

29154

American (AMR)

AF:

0.997

AC:

30429

AN:

30508

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

23156

AN:

23160

East Asian (EAS)

AF:

1.00

AC:

34360

AN:

34360

South Asian (SAS)

AF:

1.00

AC:

76053

AN:

76074

European-Finnish (FIN)

AF:

1.00

AC:

46799

AN:

46800

Middle Eastern (MID)

AF:

0.998

AC:

4957

AN:

4968

European-Non Finnish (NFE)

AF:

1.00

AC:

1061428

AN:

1061576

Other (OTH)

AF:

0.997

AC:

55986

AN:

56152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

172

259

345

431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21220

42440

63660

84880

106100

<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:

150754

AN:

152314

Hom.:

74627

Cov.:

AF XY:

0.990

AC XY:

73734

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.965

AC:

40116

AN:

41564

American (AMR)

AF:

0.995

AC:

15233

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3471

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5174

AN:

5174

South Asian (SAS)

AF:

1.00

AC:

4834

AN:

4834

European-Finnish (FIN)

AF:

1.00

AC:

10624

AN:

10624

Middle Eastern (MID)

AF:

0.993

AC:

290

AN:

292

European-Non Finnish (NFE)

AF:

1.00

AC:

68002

AN:

68016

Other (OTH)

AF:

0.994

AC:

2101

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

154

230

307

384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.995

Hom.:

15369

Bravo

AF:

0.988

Asia WGS

AF:

0.999

AC:

3463

AN:

3468

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported.

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Immunodeficiency, common variable, 10

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.5

(source)

DANN

Benign

0.35

PhyloP100

0.069

Mutation Taster

=6/94

disease causing

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over