rs727502788
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP2PP5BP4
The NM_001322934.2(NFKB2):c.2600C>T(p.Ala867Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A867A) 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 missense
NM_001322934.2 missense
Scores
2
7
8
Clinical Significance
Conservation
PhyloP100: 3.31
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001322934.2
PP2
?
Missense variant where missense usually causes diseases, NFKB2
PP5
?
Variant 10-102402273-C-T is Pathogenic according to our data. Variant chr10-102402273-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 155766.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.38146722).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NFKB2 | NM_001322934.2 | c.2600C>T | p.Ala867Val | missense_variant | 23/23 | ENST00000661543.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NFKB2 | ENST00000661543.1 | c.2600C>T | p.Ala867Val | missense_variant | 23/23 | NM_001322934.2 | P5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1402938Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 692704
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1402938
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
692704
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Immunodeficiency, common variable, 10 Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Aug 19, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 07, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 19, 2014 | - - |
Pathogenic, no assertion criteria provided | research | Samuels research lab, Centre de Recherche du CHU Ste-Justine | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with deficient anterior pituitary and variable immune deficiency (DAVID syndrome) (PMID: 25524009, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 155766). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 867 of the NFKB2 protein (p.Ala867Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 14, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Pathogenic
Sift
Benign
T;D;.
Sift4G
Benign
T;D;T
Polyphen
1.0
.;D;.
Vest4
MutPred
0.16
.;Loss of relative solvent accessibility (P = 0.0306);.;
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
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