rs2929969

Positions:

• chr8-133228454-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CCN4	NM_003882.4	c.*744G>A		3_prime_UTR_variant	5/5	ENST00000250160.11	NP_003873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCN4	ENST00000250160.11	c.*744G>A		3_prime_UTR_variant	5/5	1	NM_003882.4	ENSP00000250160.5

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127406 AN: 152028 Hom.: 53655 Cov.: 32

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: 15 AN: 16 Hom.: 7 Cov.: 0 AF XY: 0.917 AC XY: 11 AN XY: 12

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.929

GnomAD4 genome AF: 0.838 AC: 127490 AN: 152146 Hom.: 53686 Cov.: 32 AF XY: 0.830 AC XY: 61667 AN XY: 74340

Gnomad4 AFR AF: 0.891

Gnomad4 AMR AF: 0.814

Gnomad4 ASJ AF: 0.916

Gnomad4 EAS AF: 0.676

Gnomad4 SAS AF: 0.804

Gnomad4 FIN AF: 0.718

Gnomad4 NFE AF: 0.838

Gnomad4 OTH AF: 0.853

Alfa AF: 0.843 Hom.: 92348

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
DANN	Benign	0.34

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

Other links and lift over

dbSNP: rs2929969; hg19: chr8-134240697;