rs16904853

Positions:

• chr8-133220060-T-C

Variant summary

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

The NM_003882.4(CCN4):​c.350-521T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0981 in 151,644 control chromosomes in the GnomAD database, including 1,305 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 0.098 (1305 hom., cov: 32)
• Consequence: CCN4 NM_003882.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.814

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN4	NM_003882.4	c.350-521T>C		intron_variant		ENST00000250160.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN4	ENST00000250160.11	c.350-521T>C		intron_variant		1	NM_003882.4	P1

Frequencies

GnomAD3 genomes AF: 0.0980 AC: 14853 AN: 151524 Hom.: 1300 Cov.: 32

Gnomad AFR AF: 0.0697

Gnomad AMI AF: 0.0434

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0727

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0758

Gnomad OTH AF: 0.0954

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0981 AC: 14871 AN: 151644 Hom.: 1305 Cov.: 32 AF XY: 0.104 AC XY: 7718 AN XY: 74104

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0727

Gnomad4 EAS AF: 0.506

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.0896

Gnomad4 NFE AF: 0.0758

Gnomad4 OTH AF: 0.103

Alfa AF: 0.0810 Hom.: 837

Bravo AF: 0.0963

Asia WGS AF: 0.355 AC: 1230 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.80
DANN	Benign	0.66

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: rs16904853; hg19: chr8-134232303;