Genetic Variant NM_001322934.2:c.2072-3C>T (chr10-102401177-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001322934.2(NFKB2):c.2072-3C>T variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.0003899

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.84

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency, common variable, 10
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
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

NFKB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 474780.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 186 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322934.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFKB2	NM_001322934.2	MANE Select	c.2072-3C>T	splice_region intron	N/A	NP_001309863.1	Q00653-1
NFKB2	NM_001077494.3		c.2072-3C>T	splice_region intron	N/A	NP_001070962.1	Q00653-1
NFKB2	NM_001261403.3		c.2072-3C>T	splice_region intron	N/A	NP_001248332.1	Q00653-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFKB2	ENST00000661543.1	MANE Select	c.2072-3C>T	splice_region intron	N/A	ENSP00000499294.1	Q00653-1
NFKB2	ENST00000369966.8	TSL:1	c.2072-3C>T	splice_region intron	N/A	ENSP00000358983.3	Q00653-1
NFKB2	ENST00000189444.11	TSL:1	c.2072-3C>T	splice_region intron	N/A	ENSP00000189444.6	Q00653-4

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

GnomAD2 exomes

AF:

0.00154

AC:

359

AN:

232986

AF XY:

0.00174

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 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

African (AFR)

AF:

0.000304

AC:

AN:

32912

American (AMR)

AF:

0.00169

AC:

AN:

42696

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

106

AN:

24554

East Asian (EAS)

AF:

0.00

AC:

AN:

39398

South Asian (SAS)

AF:

0.000598

AC:

AN:

83654

European-Finnish (FIN)

AF:

0.000133

AC:

AN:

52610

Middle Eastern (MID)

AF:

0.00636

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00167

AC:

1836

AN:

1097456

Other (OTH)

AF:

0.00223

AC:

132

AN:

59250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

131

262

393

524

655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00122

AC:

186

AN:

152294

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41560

American (AMR)

AF:

0.00203

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00166

AC:

113

AN:

68008

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00148

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency, common variable, 10 (3)

NFKB2-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

2.8

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over