4-40119942-G-C

Position:

• chr4-40119942-G-C

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D611N) has been classified as Likely benign.

• 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

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 Likely_benign. Variant got -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/exons	MANE	UniProt
N4BP2	NM_018177.6	c.1831G>C	p.Asp611His	missense_variant	9/18	ENST00000261435.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
N4BP2	ENST00000261435.11	c.1831G>C	p.Asp611His	missense_variant	9/18	5	NM_018177.6	P1
N4BP2	ENST00000513269.1	c.772G>C	p.Asp258His	missense_variant	6/15	1
N4BP2	ENST00000511480.5	c.*1622G>C		3_prime_UTR_variant, NMD_transcript_variant	10/19	1
N4BP2	ENST00000706658.1	c.*1622G>C		3_prime_UTR_variant, NMD_transcript_variant	12/21

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000106

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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	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
MutationTaster	Benign	1.0	P
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

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

LitVar

Other links and lift over

dbSNP: rs794001; hg19: chr4-40121562;