10-102398844-G-C

Variant names:

• chr10-102398844-G-C
• NM_001322934.2:c.1097G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001322934.2(NFKB2):​c.1097G>C​(p.Gly366Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB2	NM_001322934.2	c.1097G>C	p.Gly366Ala	missense_variant	Exon 12 of 23	ENST00000661543.1	NP_001309863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1	c.1097G>C	p.Gly366Ala	missense_variant	Exon 12 of 23		NM_001322934.2	ENSP00000499294.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 10 Uncertain:1

Oct 18, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NFKB2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 366 of the NFKB2 protein (p.Gly366Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;.
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.023	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.64
MutPred		0.29		Gain of phosphorylation at Y367 (P = 0.2452);Gain of phosphorylation at Y367 (P = 0.2452);Gain of phosphorylation at Y367 (P = 0.2452);
MVP		0.46
MPC		1.1
ClinPred		0.84	D
GERP RS		5.1
Varity_R		0.24
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-104158601;