rs2929970

Positions:

• chr8-133228894-G-A
• chr8-133228894-G-C
• chr8-133228894-G-T

Variant summary

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

The NM_003882.4(CCN4):​c.*1184G>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 0.521 in 151,960 control chromosomes in the GnomAD database, including 20,907 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 (20907 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: CCN4 NM_003882.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.602

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 = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN4	NM_003882.4	c.*1184G>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.*1184G>A		3_prime_UTR_variant	5/5	1	NM_003882.4	ENSP00000250160	P1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79129 AN: 151838 Hom.: 20895 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.523

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.521 AC: 79179 AN: 151956 Hom.: 20907 Cov.: 32 AF XY: 0.514 AC XY: 38184 AN XY: 74264

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.556

Gnomad4 EAS AF: 0.618

Gnomad4 SAS AF: 0.551

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.503

Gnomad4 OTH AF: 0.526

Alfa AF: 0.470 Hom.: 5905

Bravo AF: 0.529

Asia WGS AF: 0.570 AC: 1980 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	0.58
DANN	Benign	0.70

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: rs2929970; hg19: chr8-134241137;