rs2252352

Positions:

• chr4-40126470-A-G
• chr4-40126470-A-T

Variant summary

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

The NM_018177.6(N4BP2):​c.4527+140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0803 in 492,734 control chromosomes in the GnomAD database, including 4,038 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 0.082 (941 hom., cov: 32)
  • Exomes 𝑓: 0.080 (3097 hom.)
• Consequence: N4BP2 NM_018177.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600

Genes affected

N4BP2 (HGNC:29851): (NEDD4 binding protein 2) This gene encodes a protein containing a polynucleotide kinase domain (PNK) near the N-terminal region, and a Small MutS Related (Smr) domain near the C-terminal region. The encoded protein can bind to both B-cell leukemia/lymphoma 3 (BCL-3) and neural precursor cell expressed, developmentally downregulated 4, (Nedd4) proteins. This protein binds and hydrolyzes ATP, may function as a 5'-polynucleotide kinase, and has the capacity to be a ubiquitylation substrate. This protein may play a role in transcription-coupled DNA repair or genetic recombination. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
N4BP2	NM_018177.6	c.4527+140A>G		intron_variant		ENST00000261435.11	NP_060647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
N4BP2	ENST00000261435.11	c.4527+140A>G		intron_variant		5	NM_018177.6	ENSP00000261435	P1
N4BP2	ENST00000513269.1	c.3466+140A>G		intron_variant		1		ENSP00000426430
N4BP2	ENST00000511480.5	c.*4318+140A>G		intron_variant, NMD_transcript_variant		1		ENSP00000422436
N4BP2	ENST00000706658.1	c.*4318+140A>G		intron_variant, NMD_transcript_variant				ENSP00000516486

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12443 AN: 152120 Hom.: 939 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0427

Gnomad OTH AF: 0.0831

GnomAD4 exome AF: 0.0796 AC: 27104 AN: 340496 Hom.: 3097 AF XY: 0.0806 AC XY: 14088 AN XY: 174836

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0678

Gnomad4 ASJ exome AF: 0.0786

Gnomad4 EAS exome AF: 0.453

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0220

Gnomad4 NFE exome AF: 0.0436

Gnomad4 OTH exome AF: 0.0756

GnomAD4 genome AF: 0.0819 AC: 12462 AN: 152238 Hom.: 941 Cov.: 32 AF XY: 0.0845 AC XY: 6292 AN XY: 74454

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.0675

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0428

Gnomad4 OTH AF: 0.0865

Alfa AF: 0.0489 Hom.: 47

Bravo AF: 0.0879

Asia WGS AF: 0.242 AC: 842 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.81

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: rs2252352; hg19: chr4-40128090;