Variant chr4-183099615-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024949.6(WWC2):c.124C>G(p.Arg42Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,360,504 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

WWC2
NM_024949.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWC2	NM_024949.6 linkuse as main transcript	c.124C>G	p.Arg42Gly	missense_variant	1/23	ENST00000403733.8	NP_079225.5	Q6AWC2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
WWC2	ENST00000403733.8 linkuse as main transcript	c.124C>G	p.Arg42Gly	missense_variant	1/23	5	NM_024949.6	ENSP00000384222.3	Q6AWC2-1
WWC2	ENST00000448232.6 linkuse as main transcript	c.124C>G	p.Arg42Gly	missense_variant	1/23	5		ENSP00000398577.2	Q6AWC2-6
WWC2	ENST00000513834.5 linkuse as main transcript	c.124C>G	p.Arg42Gly	missense_variant	1/23	5		ENSP00000425054.1	Q6AWC2-4
WWC2	ENST00000508614.5 linkuse as main transcript	n.124C>G		non_coding_transcript_exon_variant	1/4	3		ENSP00000423238.1	D6R9P8

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

GnomAD3 exomes

AF:

0.0000111

AC:

AN:

89776

Hom.:

AF XY:

0.0000201

AC XY:

AN XY:

49856

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000333

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1209364

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

592794

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000417

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73792

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000313

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2024

The c.124C>G (p.R42G) alteration is located in exon 1 (coding exon 1) of the WWC2 gene. This alteration results from a C to G substitution at nucleotide position 124, causing the arginine (R) at amino acid position 42 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Uncertain

0.73

D;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.3

M;M;M

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.68

P;.;.

Vest4

0.58

MutPred

0.53

Gain of glycosylation at T46 (P = 0.0053);Gain of glycosylation at T46 (P = 0.0053);Gain of glycosylation at T46 (P = 0.0053);

MVP

0.43

MPC

0.042

ClinPred

0.51

GERP RS

2.0

Varity_R

0.35

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over