rs201550645

Positions:

chr10-102401177-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001322934.2(NFKB2):c.2072-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,590,482 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

NFKB2
NM_001322934.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0003899

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.84

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]

NFKB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 10-102401177-C-T is Benign according to our data. Variant chr10-102401177-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr10-102401177-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00122 (186/152294) while in subpopulation AMR AF= 0.00203 (31/15306). AF 95% confidence interval is 0.00147. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB2	NM_001322934.2 linkuse as main transcript	c.2072-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000661543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB2	ENST00000661543.1 linkuse as main transcript	c.2072-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001322934.2	P5	Q00653-1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00154

AC:

359

AN:

232986

Hom.:

AF XY:

0.00174

AC XY:

219

AN XY:

126088

show subpopulations

Gnomad AFR exome

AF:

0.000391

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00390

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000617

Gnomad FIN exome

AF:

0.000148

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00304

GnomAD4 exome

AF:

0.00156

AC:

2249

AN:

1438188

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1171

AN XY:

712656

show subpopulations

Gnomad4 AFR exome

AF:

0.000304

Gnomad4 AMR exome

AF:

0.00169

Gnomad4 ASJ exome

AF:

0.00432

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000598

Gnomad4 FIN exome

AF:

0.000133

Gnomad4 NFE exome

AF:

0.00167

Gnomad4 OTH exome

AF:

0.00223

GnomAD4 genome

AF:

0.00122

AC:

186

AN:

152294

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00166

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00148

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 10

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 20, 2021	NFKB2 NM_001077494.3 intron 18 c.2072-3C>T:This variant has not been reported in the literature but is present in 0.1% (113/68016) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/10-102401177-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:474780). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Computational prediction tools for splicing are unclear. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

NFKB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

NFKB2: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00039

dbscSNV1_RF

Benign

0.036

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over