NM_018177.6:c.1831G>C

Variant names:

• chr4-40119942-G-C
• rs794001
• NM_018177.6:c.1831G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.913
• Publications: 31 publications found

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

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018177.6. 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
	N4BP2	NM_018177.6	MANE Select	c.1831G>C	p.Asp611His	missense	Exon 9 of 18	NP_060647.2
	N4BP2	NM_001318359.2		c.1591G>C	p.Asp531His	missense	Exon 10 of 19	NP_001305288.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	N4BP2	ENST00000261435.11	TSL:5 MANE Select	c.1831G>C	p.Asp611His	missense	Exon 9 of 18	ENSP00000261435.6
	N4BP2	ENST00000513269.1	TSL:1	c.769G>C	p.Asp257His	missense	Exon 6 of 15	ENSP00000426430.1
	N4BP2	ENST00000511480.5	TSL:1	n.*1622G>C		non_coding_transcript_exon	Exon 10 of 19	ENSP00000422436.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.10e-7 AC: 1 AN: 1234634 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 618638

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

African (AFR) AF: 0.00 AC: 0 AN: 27576

American (AMR) AF: 0.00 AC: 0 AN: 30734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20792

East Asian (EAS) AF: 0.00 AC: 0 AN: 38324

South Asian (SAS) AF: 0.00 AC: 0 AN: 68988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 941508

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.91
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.020
Sift	Uncertain	0.016	D
Sift4G	Benign	0.14	T
Polyphen		0.12	B
Vest4		0.089
MutPred		0.13		Gain of glycosylation at S616 (P = 0.014)
MVP		0.30
MPC		0.091
ClinPred		0.052	T
GERP RS		0.47
Varity_R		0.057
gMVP		0.32
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs794001; hg19: chr4-40121562;