16-69842119-C-G

Variant names:

• chr16-69842119-C-G
• rs201287506
• NM_001270454.2:c.574C>G

Variant summary

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

The NM_001270454.2(WWP2):​c.574C>G​(p.Arg192Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,610 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/24 in silico tools predict a benign outcome for this variant. 3/3 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. R192W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WWP2 NM_001270454.2 missense, splice_region
• Scores: Splicing: ADA: 0.001483
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.574C>G	p.Arg192Gly	missense splice_region	Exon 6 of 24	NP_001257383.1	O00308-1
	WWP2	NM_007014.5		c.574C>G	p.Arg192Gly	missense splice_region	Exon 7 of 25	NP_008945.2
	WWP2	NM_001270453.2		c.226C>G	p.Arg76Gly	missense splice_region	Exon 3 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.574C>G	p.Arg192Gly	missense splice_region	Exon 6 of 24	ENSP00000352069.2	O00308-1
	WWP2	ENST00000903147.1		c.574C>G	p.Arg192Gly	missense splice_region	Exon 7 of 25	ENSP00000573206.1
	WWP2	ENST00000903148.1		c.574C>G	p.Arg192Gly	missense splice_region	Exon 7 of 25	ENSP00000573207.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459610 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725852

⚠️ 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: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 85848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111038

Other (OTH) AF: 0.00 AC: 0 AN: 60326

⚠️ 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	0.13
BayesDel_addAF	Benign	-0.0080	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.23
Sift	Benign	0.37	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.81
MutPred		0.25		Loss of MoRF binding (P = 0.0315)
MVP		0.72
MPC		0.44
ClinPred		0.27	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.55
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.010		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: rs201287506; hg19: chr16-69876022;