chr8-133207820-G-A

Variant names:

• chr8-133207820-G-A
• rs2977537
• NM_003882.4:c.70-5044G>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.70-5044G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,110 control chromosomes in the GnomAD database, including 1,874 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 0.14 (1874 hom., cov: 32)
• Consequence: CCN4 NM_003882.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 21 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=-1.08).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN4	NM_003882.4	c.70-5044G>A		intron_variant	Intron 1 of 4	ENST00000250160.11	NP_003873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN4	ENST00000250160.11	c.70-5044G>A		intron_variant	Intron 1 of 4	1	NM_003882.4	ENSP00000250160.5

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21333 AN: 151992 Hom.: 1866 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.140 AC: 21361 AN: 152110 Hom.: 1874 Cov.: 32 AF XY: 0.144 AC XY: 10729 AN XY: 74346

African (AFR) AF: 0.112 AC: 4660 AN: 41500

American (AMR) AF: 0.126 AC: 1931 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3472

East Asian (EAS) AF: 0.496 AC: 2556 AN: 5152

South Asian (SAS) AF: 0.243 AC: 1169 AN: 4808

European-Finnish (FIN) AF: 0.152 AC: 1612 AN: 10586

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.123 AC: 8348 AN: 68008

Other (OTH) AF: 0.146 AC: 307 AN: 2108

Alfa AF: 0.124 Hom.: 2236

Bravo AF: 0.141

Asia WGS AF: 0.331 AC: 1150 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.081
DANN	Benign	0.46
PhyloP100		-1.5
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: rs2977537; hg19: chr8-134220063;