chr10-102396271-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

2
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.74
Variant links:
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 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 UniProt
NFKB2NM_001322934.2 linkuse as main transcriptc.40G>A p.Glu14Lys missense_variant 3/23 ENST00000661543.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NFKB2ENST00000661543.1 linkuse as main transcriptc.40G>A p.Glu14Lys missense_variant 3/23 NM_001322934.2 P5Q00653-1

Frequencies

GnomAD3 genomes
AF:
0.00403
AC:
613
AN:
152106
Hom.:
3
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 10 Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 24, 2023- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs45581936; hg19: chr10-104156028; API