8-133223573-T-C

Variant names:

• chr8-133223573-T-C
• rs2929965
• NM_003882.4:c.611-1817T>C

Variant summary

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

The NM_003882.4(CCN4):​c.611-1817T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 151,874 control chromosomes in the GnomAD database, including 26,602 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 0.59 (26602 hom., cov: 30)
• Consequence: CCN4 NM_003882.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 12 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN4	NM_003882.4	c.611-1817T>C		intron_variant	Intron 3 of 4	ENST00000250160.11	NP_003873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN4	ENST00000250160.11	c.611-1817T>C		intron_variant	Intron 3 of 4	1	NM_003882.4	ENSP00000250160.5

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89115 AN: 151758 Hom.: 26571 Cov.: 30

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.590

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

GnomAD4 genome AF: 0.587 AC: 89200 AN: 151874 Hom.: 26602 Cov.: 30 AF XY: 0.581 AC XY: 43116 AN XY: 74214

African (AFR) AF: 0.686 AC: 28425 AN: 41406

American (AMR) AF: 0.485 AC: 7399 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2352 AN: 3470

East Asian (EAS) AF: 0.588 AC: 3030 AN: 5150

South Asian (SAS) AF: 0.568 AC: 2731 AN: 4806

European-Finnish (FIN) AF: 0.476 AC: 5004 AN: 10522

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38247 AN: 67954

Other (OTH) AF: 0.593 AC: 1252 AN: 2110

Alfa AF: 0.570 Hom.: 38494

Bravo AF: 0.595

Asia WGS AF: 0.585 AC: 2036 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.48
PhyloP100		0.058
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: rs2929965; hg19: chr8-134235816;