rs727502788

Positions:

• chr10-102402273-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_001322934.2(NFKB2):​c.2600C>T​(p.Ala867Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• 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]

NFKB2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFKB2. . Gene score misZ 3.9376 (greater than the threshold 3.09). Trascript score misZ 3.5752 (greater than threshold 3.09). GenCC has associacion of gene with common variable immunodeficiency, deficiency in anterior pituitary function - variable immunodeficiency syndrome, immunodeficiency, common variable, 10.
• 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: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.
• 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	Protein	UniProt
NFKB2	NM_001322934.2	c.2600C>T	p.Ala867Val	missense_variant	23/23	ENST00000661543.1	NP_001309863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1	c.2600C>T	p.Ala867Val	missense_variant	23/23		NM_001322934.2	ENSP00000499294.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1402938 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 692704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency, common variable, 10 Pathogenic:4 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 19, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Pathogenic, no assertion criteria provided	research	Samuels research lab, Centre de Recherche du CHU Ste-Justine	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 19, 2019	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.81	.;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Pathogenic	0.68
Sift	Benign	0.12	T;D;.
Sift4G	Benign	0.17	T;D;T
Polyphen		1.0	.;D;.
Vest4		0.41
MutPred		0.16		.;Loss of relative solvent accessibility (P = 0.0306);.;
MVP		0.57
MPC		1.6
ClinPred		0.80	D
GERP RS		4.0
Varity_R		0.081
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs727502788; hg19: chr10-104162030;