Genetic Variant CCN5:p.Leu17Pro (chr20-44715440-T-C) – 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_003881.4(CCN5):c.50T>C(p.Leu17Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCN5
NM_003881.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.72

Publications

0 publications found

Variant links:

Genes affected

CCN5 (HGNC:12770): (cellular communication network factor 5) 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 (CT) domain. The encoded protein lacks the CT domain which is implicated in dimerization and heparin binding. It is 72% identical to the mouse protein at the amino acid level. This gene may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. Its expression in colon tumors is reduced while the other two WISP members are overexpressed in colon tumors. It is expressed at high levels in bone tissue, and may play an important role in modulating bone turnover. [provided by RefSeq, Jul 2008]

CCN5 links:

KCNK15-AS1 (HGNC:49901): (KCNK15 and WISP2 antisense RNA 1)

KCNK15-AS1 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, 0.756

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003881.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCN5	NM_003881.4	MANE Select	c.50T>C	p.Leu17Pro	missense	Exon 1 of 4	NP_003872.1	O76076-1
CCN5	NM_001323370.2		c.50T>C	p.Leu17Pro	missense	Exon 2 of 5	NP_001310299.1	O76076-1
CCN5	NM_001323369.2		c.50T>C	p.Leu17Pro	missense	Exon 1 of 3	NP_001310298.1	O76076-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCN5	ENST00000190983.5	TSL:1 MANE Select	c.50T>C	p.Leu17Pro	missense	Exon 1 of 4	ENSP00000190983.4	O76076-1
CCN5	ENST00000372865.4	TSL:1	c.50T>C	p.Leu17Pro	missense	Exon 1 of 3	ENSP00000361956.4	O76076-2
CCN5	ENST00000372868.6	TSL:3	c.50T>C	p.Leu17Pro	missense	Exon 2 of 5	ENSP00000361959.2	O76076-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1444050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716490

African (AFR)

AF:

0.00

AC:

AN:

33194

American (AMR)

AF:

0.00

AC:

AN:

42300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25608

East Asian (EAS)

AF:

0.00

AC:

AN:

39134

South Asian (SAS)

AF:

0.00

AC:

AN:

83092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103376

Other (OTH)

AF:

0.00

AC:

AN:

59718

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000333

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

0.0077

MutationAssessor

Uncertain

2.1

PhyloP100

4.7

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.62

Sift

Uncertain

0.017

Sift4G

Uncertain

0.049

Polyphen

0.98

Vest4

0.79

MutPred

0.67

Gain of disorder (P = 0.0106)

MVP

0.69

MPC

0.91

ClinPred

0.97

GERP RS

5.0

PromoterAI

-0.16

Neutral

(source)

Varity_R

0.73

gMVP

0.56

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over