8-133228454-G-A

Variant names:

• chr8-133228454-G-A
• rs2929969
• NM_003882.4:c.*744G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003882.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN4	NM_003882.4	MANE Select	c.*744G>A		3_prime_UTR	Exon 5 of 5	NP_003873.1
	CCN4	NR_037944.2		n.1413G>A		non_coding_transcript_exon	Exon 3 of 3
	CCN4	NM_080838.3		c.*744G>A		3_prime_UTR	Exon 4 of 4	NP_543028.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN4	ENST00000250160.11	TSL:1 MANE Select	c.*744G>A		3_prime_UTR	Exon 5 of 5	ENSP00000250160.5
	CCN4	ENST00000377862.6	TSL:1	n.*1196G>A		downstream_gene	N/A	ENSP00000367093.2

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.929 AC: 13 AN: 14

Other (OTH) AC: 0 AN: 0

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

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.021
DANN	Benign	0.34
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2929969; hg19: chr8-134240697;