Genetic Variant NM_003881.4:c.260G>C (chr20-44720096-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003881.4(CCN5):c.260G>C(p.Arg87Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,549,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CCN5
NM_003881.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.264

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.087494075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN5	NM_003881.4 link	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 4	ENST00000190983.5	NP_003872.1	O76076-1
CCN5	NM_001323370.2 link	c.260G>C	p.Arg87Pro	missense_variant	Exon 3 of 5		NP_001310299.1	O76076-1
CCN5	NM_001323369.2 link	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 3		NP_001310298.1	O76076-2
KCNK15-AS1	NR_132377.1 link	n.439-3303C>G		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN5	ENST00000190983.5 link	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 4	1	NM_003881.4	ENSP00000190983.4		O76076-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000258

AC:

AN:

154762

Hom.:

AF XY:

0.0000237

AC XY:

AN XY:

84514

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:

0.0000832

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000309

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000258

AC:

AN:

1397038

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

690960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000137

Gnomad4 FIN exome

AF:

0.0000551

Gnomad4 NFE exome

AF:

0.0000212

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000735

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000227

ExAC

AF:

0.0000346

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.073

DANN

Benign

0.84

DEOGEN2

Benign

0.089

T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.60

.;T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.087

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

N;D;N

REVEL

Benign

0.11

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.057

T;D;T

Polyphen

0.78

P;.;P

Vest4

0.19

MutPred

0.55

Gain of glycosylation at R87 (P = 0.0141);Gain of glycosylation at R87 (P = 0.0141);Gain of glycosylation at R87 (P = 0.0141);

MVP

0.15

MPC

0.50

ClinPred

0.068

GERP RS

-2.4

Varity_R

0.18

gMVP

0.56

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over