Genetic Variant NM_018177.6:c.1831G>C (chr4-40119942-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018177.6(N4BP2):c.1831G>C(p.Asp611His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000081 in 1,234,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

N4BP2
NM_018177.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.913

Publications

31 publications found

Variant links:

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]

N4BP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040659964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
N4BP2	NM_018177.6 link	c.1831G>C	p.Asp611His	missense_variant	Exon 9 of 18	ENST00000261435.11	NP_060647.2	Q86UW6-1B2ZZ87

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
N4BP2	ENST00000261435.11 link	c.1831G>C	p.Asp611His	missense_variant	Exon 9 of 18	5	NM_018177.6	ENSP00000261435.6		Q86UW6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.10e-7

AC:

AN:

1234634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

618638

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27576

American (AMR)

AF:

0.00

AC:

AN:

30734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20792

East Asian (EAS)

AF:

0.00

AC:

AN:

38324

South Asian (SAS)

AF:

0.00

AC:

AN:

68988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.00000106

AC:

AN:

941508

Other (OTH)

AF:

0.00

AC:

AN:

51830

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0014

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.42

M_CAP

Benign

0.0067

MetaRNN

Benign

0.041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.91

PrimateAI

Benign

0.30

PROVEAN

Benign

0.44

REVEL

Benign

0.020

Sift

Uncertain

0.016

Sift4G

Benign

0.14

Polyphen

0.12

Vest4

0.089

MutPred

0.13

Gain of glycosylation at S616 (P = 0.014);

MVP

0.30

MPC

0.091

ClinPred

0.052

GERP RS

0.47

Varity_R

0.057

gMVP

0.32

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over