10-102399458-C-A

Variant names:

• chr10-102399458-C-A
• rs202001697
• NM_001322934.2:c.1288C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001322934.2(NFKB2):​c.1288C>A​(p.Pro430Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,355,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P430S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• Publications: 0 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, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105917394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB2	NM_001322934.2	c.1288C>A	p.Pro430Thr	missense_variant	Exon 13 of 23	ENST00000661543.1	NP_001309863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1	c.1288C>A	p.Pro430Thr	missense_variant	Exon 13 of 23		NM_001322934.2	ENSP00000499294.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1355796 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 665192

African (AFR) AF: 0.00 AC: 0 AN: 28674

American (AMR) AF: 0.00 AC: 0 AN: 30114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22738

East Asian (EAS) AF: 0.00 AC: 0 AN: 33768

South Asian (SAS) AF: 0.00 AC: 0 AN: 75232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5214

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1057820

Other (OTH) AF: 0.00 AC: 0 AN: 55848

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.0
DANN	Benign	0.75
DEOGEN2	Benign	0.10	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.70	T;T;.
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L;L;L
PhyloP100		1.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.37	N;N;N
REVEL	Benign	0.077
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.011	.;B;.
Vest4		0.23
MutPred		0.16		Gain of phosphorylation at P430 (P = 0.0177);Gain of phosphorylation at P430 (P = 0.0177);Gain of phosphorylation at P430 (P = 0.0177);
MVP		0.34
MPC		0.69
ClinPred		0.085	T
GERP RS		3.6
Varity_R		0.021
gMVP		0.30
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs202001697; hg19: chr10-104159215;