dbSNP rs2929969: CCN4:c.*744G>A (chr8-133228454-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003882.4(CCN4):c.*744G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 152,162 control chromosomes in the GnomAD database, including 53,693 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.84 ( 53686 hom., cov: 32)

Exomes 𝑓: 0.94 ( 7 hom. )

Consequence

CCN4
NM_003882.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.79

Publications

8 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN4	NM_003882.4 link	c.*744G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000250160.11	NP_003873.1	O95388-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN4	ENST00000250160.11 link	c.*744G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_003882.4	ENSP00000250160.5		O95388-1
CCN4	ENST00000377862.6 link	n.*1196G>A		downstream_gene_variant		1		ENSP00000367093.2		E5RG88

Frequencies

GnomAD3 genomes

AF:

0.838

AC:

127406

AN:

152028

Hom.:

53655

Cov.:

show subpopulations

Gnomad AFR

AF:

0.892

Gnomad AMI

AF:

0.931

Gnomad AMR

AF:

0.814

Gnomad ASJ

AF:

0.916

Gnomad EAS

AF:

0.676

Gnomad SAS

AF:

0.805

Gnomad FIN

AF:

0.718

Gnomad MID

AF:

0.908

Gnomad NFE

AF:

0.838

Gnomad OTH

AF:

0.853

GnomAD4 exome

AF:

0.938

AC:

AN:

Hom.:

Cov.:

AF XY:

0.917

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.929

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

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

GnomAD4 genome

AF:

0.838

AC:

127490

AN:

152146

Hom.:

53686

Cov.:

AF XY:

0.830

AC XY:

61667

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.891

AC:

37005

AN:

41516

American (AMR)

AF:

0.814

AC:

12448

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.916

AC:

3179

AN:

3472

East Asian (EAS)

AF:

0.676

AC:

3481

AN:

5152

South Asian (SAS)

AF:

0.804

AC:

3880

AN:

4826

European-Finnish (FIN)

AF:

0.718

AC:

7578

AN:

10554

Middle Eastern (MID)

AF:

0.901

AC:

265

AN:

294

European-Non Finnish (NFE)

AF:

0.838

AC:

57004

AN:

68018

Other (OTH)

AF:

0.853

AC:

1801

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1047

2094

3140

4187

5234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<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:

0.840

Hom.:

219469

Bravo

AF:

0.849

Asia WGS

AF:

0.736

AC:

2560

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.021

(source)

DANN

Benign

0.34

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over