19-38905415-G-C

Variant names:

• chr19-38905415-G-C
• rs759687798
• NM_002503.5:c.499G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002503.5(NFKBIB):​c.499G>C​(p.Asp167His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D167N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NFKBIB NM_002503.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.41
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18583363).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002503.5. 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
	NFKBIB	NM_002503.5	MANE Select	c.499G>C	p.Asp167His	missense	Exon 3 of 6	NP_002494.2
	NFKBIB	NM_001369699.1		c.499G>C	p.Asp167His	missense	Exon 3 of 5	NP_001356628.1	Q15653-2
	NFKBIB	NM_001243116.2		c.241G>C	p.Asp81His	missense	Exon 3 of 6	NP_001230045.1	G5E9C2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIB	ENST00000313582.6	TSL:1 MANE Select	c.499G>C	p.Asp167His	missense	Exon 3 of 6	ENSP00000312988.5	Q15653-1
	NFKBIB	ENST00000572515.5	TSL:1	c.499G>C	p.Asp167His	missense	Exon 3 of 5	ENSP00000459728.1	Q15653-2
	NFKBIB	ENST00000392079.7	TSL:5	c.241G>C	p.Asp81His	missense	Exon 3 of 6	ENSP00000375929.4	G5E9C2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.15
Sift	Uncertain	0.029	D
Sift4G	Benign	0.18	T
Polyphen		0.43	B
Vest4		0.61
MutPred		0.17		Gain of glycosylation at T169 (P = 0.0946)
MVP		0.70
MPC		0.38
ClinPred		0.39	T
GERP RS		3.2
Varity_R		0.046
gMVP		0.46
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs759687798; hg19: chr19-39396055;