rs2233437

Positions:

• chr6-44260425-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004556.3(NFKBIE):​c.780+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 1,613,518 control chromosomes in the GnomAD database, including 147,208 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (11255 hom., cov: 32)
  • Exomes 𝑓: 0.43 (135953 hom.)
• Consequence: NFKBIE NM_004556.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.804

Genes affected

NFKBIE (HGNC:7799): (NFKB inhibitor epsilon) The protein encoded by this gene binds to components of NF-kappa-B, trapping the complex in the cytoplasm and preventing it from activating genes in the nucleus. Phosphorylation of the encoded protein targets it for destruction by the ubiquitin pathway, which activates NF-kappa-B by making it available to translocate to the nucleus. [provided by RefSeq, Sep 2011]

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIE	NM_004556.3	c.780+26C>T		intron_variant		ENST00000619360.6	NP_004547.3
POLR1C	NM_001318876.2	c.946-181465G>A		intron_variant			NP_001305805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIE	ENST00000619360.6	c.780+26C>T		intron_variant		1	NM_004556.3	ENSP00000480216.1
NFKBIE	ENST00000275015.9	c.1197+26C>T		intron_variant		1		ENSP00000275015.3
NFKBIE	ENST00000477930.2	n.*277C>T		downstream_gene_variant		3		ENSP00000454778.2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53774 AN: 151948 Hom.: 11247 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.391

GnomAD3 exomes AF: 0.427 AC: 107217 AN: 251020 Hom.: 24203 AF XY: 0.428 AC XY: 58086 AN XY: 135672

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.589

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.379

Gnomad SAS exome AF: 0.413

Gnomad FIN exome AF: 0.433

Gnomad NFE exome AF: 0.432

Gnomad OTH exome AF: 0.450

GnomAD4 exome AF: 0.427 AC: 623757 AN: 1461452 Hom.: 135953 Cov.: 38 AF XY: 0.427 AC XY: 310469 AN XY: 727032

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.581

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.431

Gnomad4 SAS exome AF: 0.414

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.431

Gnomad4 OTH exome AF: 0.416

GnomAD4 genome AF: 0.354 AC: 53787 AN: 152066 Hom.: 11255 Cov.: 32 AF XY: 0.361 AC XY: 26826 AN XY: 74302

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.515

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.422

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.430

Gnomad4 OTH AF: 0.388

Alfa AF: 0.403 Hom.: 4310

Bravo AF: 0.349

Asia WGS AF: 0.399 AC: 1385 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.36
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs2233437; hg19: chr6-44228162; COSMIC: COSV51490299; COSMIC: COSV51490299;