chr16-69840261-A-G

Variant names:

• chr16-69840261-A-G
• rs757130733
• NM_001270454.2:c.476A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001270454.2(WWP2):​c.476A>G​(p.Asp159Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000711 in 1,406,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. D159A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: WWP2 NM_001270454.2 missense, splice_region
• Scores: Splicing: ADA: 0.1520
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38
• Publications: 2 publications found

Genes affected

WWP2 (HGNC:16804): (WW domain containing E3 ubiquitin protein ligase 2) This gene encodes a member of the Nedd4 family of E3 ligases, which play an important role in protein ubiquitination. The encoded protein contains four WW domains and may play a role in multiple processes including chondrogenesis and the regulation of oncogenic signaling pathways via interactions with Smad proteins and the tumor suppressor PTEN. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 10. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21236405).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270454.2. 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
	WWP2	NM_001270454.2	MANE Select	c.476A>G	p.Asp159Gly	missense splice_region	Exon 5 of 24	NP_001257383.1	O00308-1
	WWP2	NM_007014.5		c.476A>G	p.Asp159Gly	missense splice_region	Exon 6 of 25	NP_008945.2
	WWP2	NM_001270453.2		c.128A>G	p.Asp43Gly	missense splice_region	Exon 2 of 21	NP_001257382.1	O00308-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWP2	ENST00000359154.7	TSL:1 MANE Select	c.476A>G	p.Asp159Gly	missense splice_region	Exon 5 of 24	ENSP00000352069.2	O00308-1
	WWP2	ENST00000903147.1		c.476A>G	p.Asp159Gly	missense splice_region	Exon 6 of 25	ENSP00000573206.1
	WWP2	ENST00000903148.1		c.476A>G	p.Asp159Gly	missense splice_region	Exon 6 of 25	ENSP00000573207.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251326 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406396 Hom.: 0 Cov.: 38 AF XY: 0.00000143 AC XY: 1 AN XY: 699490

African (AFR) AF: 0.00 AC: 0 AN: 31726

American (AMR) AF: 0.00 AC: 0 AN: 42786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23930

East Asian (EAS) AF: 0.00 AC: 0 AN: 35746

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5360

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077062

Other (OTH) AF: 0.00 AC: 0 AN: 56294

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Benign	0.050
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		6.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.14
Sift	Benign	0.064	T
Sift4G	Benign	0.17	T
Polyphen		0.039	B
Vest4		0.33
MutPred		0.17		Gain of catalytic residue at S161 (P = 0.0704)
MVP		0.36
MPC		0.45
ClinPred		0.55	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: -1

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

Other links and lift over

dbSNP: rs757130733; hg19: chr16-69874164;