chr6-44264996-G-A

Variant names:

• chr6-44264996-G-A
• rs2233435
• NM_004556.3:c.351C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004556.3(NFKBIE):​c.351C>T​(p.Ser117Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,575,478 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: NFKBIE NM_004556.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.87
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 6-44264996-G-A is Benign according to our data. Variant chr6-44264996-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 723585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.87 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004556.3. 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
	NFKBIE	NM_004556.3	MANE Select	c.351C>T	p.Ser117Ser	synonymous	Exon 1 of 6	NP_004547.3	Q7LC14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIE	ENST00000619360.6	TSL:1 MANE Select	c.351C>T	p.Ser117Ser	synonymous	Exon 1 of 6	ENSP00000480216.1	Q7LC14
	NFKBIE	ENST00000275015.9	TSL:1	c.768C>T	p.Ser256Ser	synonymous	Exon 1 of 6	ENSP00000275015.3	O00221
	NFKBIE	ENST00000890578.1		c.351C>T	p.Ser117Ser	synonymous	Exon 1 of 6	ENSP00000560637.1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152162 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00818

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000659 AC: 124 AN: 188192 AF XY: 0.000487

Gnomad AFR exome AF: 0.00940

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000685

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.000411

GnomAD4 exome AF: 0.000274 AC: 390 AN: 1423198 Hom.: 2 Cov.: 32 AF XY: 0.000230 AC XY: 162 AN XY: 704150

African (AFR) AF: 0.00912 AC: 303 AN: 33228

American (AMR) AF: 0.000343 AC: 13 AN: 37952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25296

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38550

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49762

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5718

European-Non Finnish (NFE) AF: 0.0000275 AC: 30 AN: 1092622

Other (OTH) AF: 0.000661 AC: 39 AN: 58970

GnomAD4 genome AF: 0.00236 AC: 360 AN: 152280 Hom.: 3 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74464

African (AFR) AF: 0.00827 AC: 344 AN: 41578

American (AMR) AF: 0.000653 AC: 10 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67998

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000755 Hom.: 0

Bravo AF: 0.00293

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.35
DANN	Benign	0.93
PhyloP100		-3.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2233435; hg19: chr6-44232733;