chr8-133196596-A-T

Variant names:

• chr8-133196596-A-T
• rs2977519
• NM_003882.4:c.69+5383A>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.69+5383A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 152,022 control chromosomes in the GnomAD database, including 23,533 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 0.53 (23533 hom., cov: 31)
• Consequence: CCN4 NM_003882.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0720
• Publications: 6 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN4	NM_003882.4	c.69+5383A>T		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.69+5383A>T		intron_variant	Intron 1 of 4	1	NM_003882.4	ENSP00000250160.5

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80877 AN: 151904 Hom.: 23531 Cov.: 31

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.558

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

GnomAD4 genome AF: 0.532 AC: 80908 AN: 152022 Hom.: 23533 Cov.: 31 AF XY: 0.533 AC XY: 39568 AN XY: 74288

African (AFR) AF: 0.311 AC: 12898 AN: 41448

American (AMR) AF: 0.507 AC: 7750 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2350 AN: 3472

East Asian (EAS) AF: 0.282 AC: 1459 AN: 5172

South Asian (SAS) AF: 0.581 AC: 2802 AN: 4822

European-Finnish (FIN) AF: 0.646 AC: 6819 AN: 10558

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44797 AN: 67962

Other (OTH) AF: 0.558 AC: 1179 AN: 2112

Alfa AF: 0.580 Hom.: 3338

Bravo AF: 0.509

Asia WGS AF: 0.441 AC: 1535 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.49
DANN	Benign	0.52
PhyloP100		-0.072
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: rs2977519; hg19: chr8-134208839;