8-133229790-C-T

Variant names:

• chr8-133229790-C-T
• rs2977549
• NM_003882.4:c.*2080C>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.*2080C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 152,094 control chromosomes in the GnomAD database, including 20,642 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 0.52 (20642 hom., cov: 34)
  • Failed GnomAD Quality Control
• Consequence: CCN4 NM_003882.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.368
• 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN4	NM_003882.4	c.*2080C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000250160.11	NP_003873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN4	ENST00000250160.11	c.*2080C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_003882.4	ENSP00000250160.5

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78697 AN: 151976 Hom.: 20632 Cov.: 34

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.519

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.518 AC: 78743 AN: 152094 Hom.: 20642 Cov.: 34 AF XY: 0.511 AC XY: 37975 AN XY: 74334

African (AFR) AF: 0.575 AC: 23867 AN: 41496

American (AMR) AF: 0.454 AC: 6935 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1928 AN: 3470

East Asian (EAS) AF: 0.618 AC: 3201 AN: 5178

South Asian (SAS) AF: 0.552 AC: 2660 AN: 4820

European-Finnish (FIN) AF: 0.395 AC: 4176 AN: 10572

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

European-Non Finnish (NFE) AF: 0.504 AC: 34225 AN: 67960

Other (OTH) AF: 0.522 AC: 1101 AN: 2110

Alfa AF: 0.353 Hom.: 913

Bravo AF: 0.525

Asia WGS AF: 0.570 AC: 1981 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.3
DANN	Benign	0.74
PhyloP100		-0.37
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: rs2977549; hg19: chr8-134242033;