chr16-69842059-G-C

Variant names:

• chr16-69842059-G-C
• rs147074353
• NM_001270454.2:c.514G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001270454.2(WWP2):​c.514G>C​(p.Ala172Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,613,498 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: WWP2 NM_001270454.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.740
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015009463).
• BS2: High AC in GnomAd4 at 80 AD gene.

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.514G>C	p.Ala172Pro	missense	Exon 6 of 24	NP_001257383.1	O00308-1
	WWP2	NM_007014.5		c.514G>C	p.Ala172Pro	missense	Exon 7 of 25	NP_008945.2
	WWP2	NM_001270453.2		c.166G>C	p.Ala56Pro	missense	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.514G>C	p.Ala172Pro	missense	Exon 6 of 24	ENSP00000352069.2	O00308-1
	WWP2	ENST00000903147.1		c.514G>C	p.Ala172Pro	missense	Exon 7 of 25	ENSP00000573206.1
	WWP2	ENST00000903148.1		c.514G>C	p.Ala172Pro	missense	Exon 7 of 25	ENSP00000573207.1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000515 AC: 128 AN: 248738 AF XY: 0.000586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.000981

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000467 AC: 683 AN: 1461160 Hom.: 1 Cov.: 30 AF XY: 0.000513 AC XY: 373 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000448 AC: 2 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86142

European-Finnish (FIN) AF: 0.000696 AC: 37 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000553 AC: 615 AN: 1111786

Other (OTH) AF: 0.000348 AC: 21 AN: 60380

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74498

African (AFR) AF: 0.0000481 AC: 2 AN: 41582

American (AMR) AF: 0.000654 AC: 10 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000759 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.74
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.18
Sift	Benign	0.28	T
Sift4G	Benign	0.099	T
Polyphen		0.072	B
Vest4		0.48
MVP		0.31
MPC		0.48
ClinPred		0.018	T
GERP RS		-0.22
Varity_R		0.036
gMVP		0.33
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147074353; hg19: chr16-69875962; COSMIC: COSV106506129; COSMIC: COSV106506129;