rs2977536

Variant names:

• chr8-133207034-G-C
• rs2977536
• NM_003882.4:c.70-5830G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-133207034-G-C
• chr8-133207034-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003882.4(CCN4):​c.70-5830G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 152,124 control chromosomes in the GnomAD database, including 11,061 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 0.36 (11061 hom., cov: 32)
• Consequence: CCN4 NM_003882.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220
• 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 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.70-5830G>C		intron	N/A	NP_003873.1
	CCN4	NM_080838.3		c.70-5830G>C		intron	N/A	NP_543028.1
	CCN4	NM_001204869.2		c.70-5830G>C		intron	N/A	NP_001191798.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN4	ENST00000250160.11	TSL:1 MANE Select	c.70-5830G>C		intron	N/A	ENSP00000250160.5
	CCN4	ENST00000220856.6	TSL:1	c.70-5830G>C		intron	N/A	ENSP00000220856.6
	CCN4	ENST00000517423.5	TSL:1	c.70-5830G>C		intron	N/A	ENSP00000427744.1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55325 AN: 152006 Hom.: 11042 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.407

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

GnomAD4 genome AF: 0.364 AC: 55358 AN: 152124 Hom.: 11061 Cov.: 32 AF XY: 0.368 AC XY: 27388 AN XY: 74356

African (AFR) AF: 0.205 AC: 8499 AN: 41498

American (AMR) AF: 0.404 AC: 6172 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1591 AN: 3472

East Asian (EAS) AF: 0.689 AC: 3545 AN: 5146

South Asian (SAS) AF: 0.462 AC: 2230 AN: 4826

European-Finnish (FIN) AF: 0.396 AC: 4190 AN: 10594

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27728 AN: 67988

Other (OTH) AF: 0.411 AC: 869 AN: 2114

Alfa AF: 0.359 Hom.: 1249

Bravo AF: 0.362

Asia WGS AF: 0.568 AC: 1979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.97
DANN	Benign	0.41
PhyloP100		-0.022
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: rs2977536; hg19: chr8-134219277; COSMIC: COSV51535281;