10-102399466-C-T

Variant names:

• chr10-102399466-C-T
• rs192635220
• NM_001322934.2:c.1296C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001322934.2(NFKB2):​c.1296C>T​(p.Cys432Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,501,706 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: NFKB2 NM_001322934.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.544
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 10-102399466-C-T is Benign according to our data. Variant chr10-102399466-C-T is described in ClinVar as Benign. ClinVar VariationId is 541631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.544 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000643 (98/152338) while in subpopulation EAS AF = 0.0137 (71/5180). AF 95% confidence interval is 0.0111. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 98 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	NM_001322934.2	MANE Select	c.1296C>T	p.Cys432Cys	synonymous	Exon 13 of 23	NP_001309863.1	Q00653-1
	NFKB2	NM_001077494.3		c.1296C>T	p.Cys432Cys	synonymous	Exon 13 of 23	NP_001070962.1	Q00653-1
	NFKB2	NM_001261403.3		c.1296C>T	p.Cys432Cys	synonymous	Exon 12 of 22	NP_001248332.1	Q00653-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB2	ENST00000661543.1	MANE Select	c.1296C>T	p.Cys432Cys	synonymous	Exon 13 of 23	ENSP00000499294.1	Q00653-1
	NFKB2	ENST00000369966.8	TSL:1	c.1296C>T	p.Cys432Cys	synonymous	Exon 13 of 23	ENSP00000358983.3	Q00653-1
	NFKB2	ENST00000189444.11	TSL:1	c.1296C>T	p.Cys432Cys	synonymous	Exon 13 of 23	ENSP00000189444.6	Q00653-4

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00103 AC: 106 AN: 102544 AF XY: 0.000915

Gnomad AFR exome AF: 0.000531

Gnomad AMR exome AF: 0.0000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000278

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.000206 AC: 278 AN: 1349368 Hom.: 2 Cov.: 35 AF XY: 0.000209 AC XY: 138 AN XY: 661504

African (AFR) AF: 0.000211 AC: 6 AN: 28404

American (AMR) AF: 0.0000342 AC: 1 AN: 29218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22266

East Asian (EAS) AF: 0.00590 AC: 198 AN: 33586

South Asian (SAS) AF: 0.000365 AC: 27 AN: 74050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5190

European-Non Finnish (NFE) AF: 0.00000663 AC: 7 AN: 1055094

Other (OTH) AF: 0.000701 AC: 39 AN: 55644

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152338 Hom.: 1 Cov.: 33 AF XY: 0.000712 AC XY: 53 AN XY: 74490

African (AFR) AF: 0.000577 AC: 24 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0137 AC: 71 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000484

Asia WGS AF: 0.00722 AC: 25 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency, common variable, 10 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs192635220; hg19: chr10-104159223;