Variant 8-133213117-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000250160.11(CCN4):c.323C>T(p.Pro108Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,460,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CCN4
ENST00000250160.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96

Variant links:

Genes affected

CCN4 (HGNC:12769): (cellular communication network factor 4) This gene encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. WNT1 is a member of a family of cysteine-rich, glycosylated signaling proteins that mediate diverse developmental processes. The CTGF family members are characterized by four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like domain. This gene may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. It is expressed at a high level in fibroblast cells, and overexpressed in colon tumors. The encoded protein binds to decorin and biglycan, two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue, and possibly prevents the inhibitory activity of decorin and biglycan in tumor cell proliferation. It also attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. It is 83% identical to the mouse protein at the amino acid level. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2011]

CCN4 links:

Genome browser will be placed here

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
CCN4	NM_003882.4 linkuse as main transcript	c.323C>T	p.Pro108Leu	missense_variant	2/5	ENST00000250160.11	NP_003873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCN4	ENST00000250160.11 linkuse as main transcript	c.323C>T	p.Pro108Leu	missense_variant	2/5	1	NM_003882.4	ENSP00000250160	P1	O95388-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

250260

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135436

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460808

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726482

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Mar 31, 2024

The c.323C>T (p.P108L) alteration is located in exon 2 (coding exon 2) of the WISP1 gene. This alteration results from a C to T substitution at nucleotide position 323, causing the proline (P) at amino acid position 108 to be replaced by a leucine (L). 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

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Uncertain

0.048

MutationAssessor

Uncertain

2.4

M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.1

D;D;D

REVEL

Uncertain

0.50

Sift

Benign

0.037

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.67

MutPred

0.53

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.66

MPC

0.64

ClinPred

0.97

GERP RS

5.3

Varity_R

0.52

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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