rs397514332
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_StrongPS3PM2PP5_Very_Strong
The NM_001322934.2(NFKB2):c.2557C>T(p.Arg853*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000773792: Experimental studies have shown that this premature translational stop signal affects NFKB2 function (PMID:24140114, 28778864)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R853R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NFKB2
NM_001322934.2 stop_gained
NM_001322934.2 stop_gained
Scores
2
2
2
Clinical Significance
Conservation
PhyloP100: 0.458
Publications
19 publications found
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, 10Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
- common variable immunodeficiencyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- deficiency in anterior pituitary function - variable immunodeficiency syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
PS3
PS3 evidence extracted from ClinVar submissions: SCV000773792: Experimental studies have shown that this premature translational stop signal affects NFKB2 function (PMID: 24140114, 28778864).; SCV002549308: "In vitro assays demonstrated that R853X has a dominant negative effect (Kuehn et al., 2017);"; SCV001338047: Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this C-terminal truncation indeed affects normal protein function (Chen_2013, Kuehn_2017).
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-102402138-C-T is Pathogenic according to our data. Variant chr10-102402138-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 65385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NFKB2 | MANE Select | c.2557C>T | p.Arg853* | stop_gained | Exon 22 of 23 | NP_001309863.1 | Q00653-1 | ||
| NFKB2 | c.2557C>T | p.Arg853* | stop_gained | Exon 22 of 23 | NP_001070962.1 | Q00653-1 | |||
| NFKB2 | c.2557C>T | p.Arg853* | stop_gained | Exon 21 of 22 | NP_001248332.1 | Q00653-4 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NFKB2 | MANE Select | c.2557C>T | p.Arg853* | stop_gained | Exon 22 of 23 | ENSP00000499294.1 | Q00653-1 | ||
| NFKB2 | TSL:1 | c.2557C>T | p.Arg853* | stop_gained | Exon 22 of 23 | ENSP00000358983.3 | Q00653-1 | ||
| NFKB2 | TSL:1 | c.2557C>T | p.Arg853* | stop_gained | Exon 22 of 23 | ENSP00000189444.6 | Q00653-4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1425178Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 705554
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1425178
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
705554
African (AFR)
AF:
AC:
0
AN:
32698
American (AMR)
AF:
AC:
0
AN:
39322
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25406
East Asian (EAS)
AF:
AC:
0
AN:
37664
South Asian (SAS)
AF:
AC:
0
AN:
81292
European-Finnish (FIN)
AF:
AC:
0
AN:
50922
Middle Eastern (MID)
AF:
AC:
0
AN:
5730
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1093126
Other (OTH)
AF:
AC:
0
AN:
59018
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
9
-
-
Immunodeficiency, common variable, 10 (9)
2
-
-
not provided (2)
1
-
-
Common variable immunodeficiency (1)
1
-
-
Inherited Immunodeficiency Diseases (1)
1
-
-
not specified (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
PhyloP100
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
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.