19-38908768-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002503.5(NFKBIB):c.1007G>A(p.Ser336Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NFKBIB NM_002503.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

Genes affected

NFKBIB (HGNC:7798): (NFKB inhibitor beta) The protein encoded by this gene belongs to the NF-kappa-B inhibitor family, which inhibit NF-kappa-B by complexing with, and trapping it in the cytoplasm. Phosphorylation of serine residues on these proteins by kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B, which translocates to the nucleus to function as a transcription factor. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13645718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIB	NM_002503.5	c.1007G>A	p.Ser336Asn	missense_variant	6/6	ENST00000313582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIB	ENST00000313582.6	c.1007G>A	p.Ser336Asn	missense_variant	6/6	1	NM_002503.5	P1
NFKBIB	ENST00000392079.7	c.749G>A	p.Ser250Asn	missense_variant	6/6	5
NFKBIB	ENST00000509705.3	c.*1824G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.1007G>A (p.S336N) alteration is located in exon 6 (coding exon 6) of the NFKBIB gene. This alteration results from a G to A substitution at nucleotide position 1007, causing the serine (S) at amino acid position 336 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	17
Dann	Uncertain	0.98
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	.;B
Vest4		0.29
MutPred		0.13		.;Loss of phosphorylation at S336 (P = 0.0148);
MVP		0.50
MPC		0.33
ClinPred		0.19	T
GERP RS		2.9
Varity_R		0.10
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39399408; COSMIC: COSV58003986; COSMIC: COSV58003986;