10-102396271-G-A

Position:

• chr10-102396271-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001322934.2(NFKB2):​c.40G>A​(p.Glu14Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000841 in 1,612,586 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (3 hom.)
• Consequence: NFKB2 NM_001322934.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.74

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 Benign. Variant got -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006150514).
• BP6: Variant 10-102396271-G-A is Benign according to our data. Variant chr10-102396271-G-A is described in ClinVar as [Benign]. Clinvar id is 474786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102396271-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00405 (617/152224) while in subpopulation AFR AF= 0.0136 (566/41538). AF 95% confidence interval is 0.0127. There are 4 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 617 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB2	NM_001322934.2	c.40G>A	p.Glu14Lys	missense_variant	3/23	ENST00000661543.1	NP_001309863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB2	ENST00000661543.1	c.40G>A	p.Glu14Lys	missense_variant	3/23		NM_001322934.2	ENSP00000499294	P5

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152106 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00119 AC: 298 AN: 249404 Hom.: 2 AF XY: 0.000902 AC XY: 122 AN XY: 135302

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00547

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000506 AC: 739 AN: 1460362 Hom.: 3 Cov.: 33 AF XY: 0.000467 AC XY: 339 AN XY: 726134

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.000694

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00405 AC: 617 AN: 152224 Hom.: 4 Cov.: 31 AF XY: 0.00388 AC XY: 289 AN XY: 74420

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000778 Hom.: 0

Bravo AF: 0.00467

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0132 AC: 50

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00139 AC: 168

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T;.;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.66	T;D;D;.;.
MetaRNN	Benign	0.0062	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;L;L;.;L
MutationTaster	Benign	0.92	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.62	.;N;N;.;N
REVEL	Benign	0.018
Sift	Benign	0.051	.;T;T;.;T
Sift4G	Benign	0.12	T;D;D;T;D
Polyphen		0.12	.;.;B;.;.
Vest4		0.31, 0.32, 0.31
MVP		0.52
MPC		1.4
ClinPred		0.024	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs45581936; hg19: chr10-104156028;