8-133229790-C-T

Variant summary

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

The NM_003882.4(CCN4):c.*2080C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 152,094 control chromosomes in the GnomAD database, including 20,642 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 0.52 (20642 hom., cov: 34)
  • Failed GnomAD Quality Control
• Consequence: CCN4 NM_003882.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.368

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN4	NM_003882.4	c.*2080C>T		3_prime_UTR_variant	5/5	ENST00000250160.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN4	ENST00000250160.11	c.*2080C>T		3_prime_UTR_variant	5/5	1	NM_003882.4	P1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78697 AN: 151976 Hom.: 20632 Cov.: 34

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.519

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.518 AC: 78743 AN: 152094 Hom.: 20642 Cov.: 34 AF XY: 0.511 AC XY: 37975 AN XY: 74334

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.556

Gnomad4 EAS AF: 0.618

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.504

Gnomad4 OTH AF: 0.522

Alfa AF: 0.333 Hom.: 773

Bravo AF: 0.525

Asia WGS AF: 0.570 AC: 1981 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	4.3
Dann	Benign	0.74

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: rs2977549; hg19: chr8-134242033;