Genetic Variant NM_024949.6:c.124C>T (chr4-183099615-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024949.6(WWC2):c.124C>T(p.Arg42Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,360,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R42G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

WWC2
NM_024949.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.62

Publications

1 publications found

Variant links:

Genes affected

WWC2 (HGNC:24148): (WW and C2 domain containing 2) This gene encodes a member of the WW-and-C2-domain-containing family of proteins. Members of this family have two N-terminal WW domains that mediate binding to target proteins harboring L/PPxY motifs, an internal C2 domain for membrane association, and C-terminal alpha protein kinase C binding sites and class III PDZ domain-interaction motifs. Proteins of this family are able to form homo- and heterodimers and to modulate hippo pathway signaling. [provided by RefSeq, Sep 2016]

WWC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024949.6. 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
	WWC2	NM_024949.6	MANE Select	c.124C>T	p.Arg42Trp	missense	Exon 1 of 23	NP_079225.5
	WWC2	NM_001410864.1		c.124C>T	p.Arg42Trp	missense	Exon 1 of 23	NP_001397793.1	Q6AWC2-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WWC2	ENST00000403733.8	TSL:5 MANE Select	c.124C>T	p.Arg42Trp	missense	Exon 1 of 23	ENSP00000384222.3	Q6AWC2-1
WWC2	ENST00000962606.1		c.124C>T	p.Arg42Trp	missense	Exon 1 of 23	ENSP00000632665.1
WWC2	ENST00000448232.6	TSL:5	c.124C>T	p.Arg42Trp	missense	Exon 1 of 23	ENSP00000398577.2	Q6AWC2-6

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.27e-7

AC:

AN:

1209364

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

592794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24758

American (AMR)

AF:

0.00

AC:

AN:

23964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19058

East Asian (EAS)

AF:

0.00

AC:

AN:

24284

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4810

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

970848

Other (OTH)

AF:

0.00

AC:

AN:

47112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73792

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67668

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.73

Eigen

Benign

0.15

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.48

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.66

MutationAssessor

Pathogenic

4.4

PhyloP100

1.6

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.59

MutPred

0.49

Gain of glycosylation at T46 (P = 0.0053)

MVP

0.54

MPC

0.079

ClinPred

1.0

GERP RS

2.0

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.2

Varity_R

0.28

gMVP

0.46

Mutation Taster

=73/27

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over