8-133220707-G-A

Position:

• chr8-133220707-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003882.4(CCN4):​c.476G>A​(p.Arg159Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,788 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: CCN4 NM_003882.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.66

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010828257).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN4	NM_003882.4	c.476G>A	p.Arg159Gln	missense_variant	3/5	ENST00000250160.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN4	ENST00000250160.11	c.476G>A	p.Arg159Gln	missense_variant	3/5	1	NM_003882.4	P1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000567 AC: 142 AN: 250470 Hom.: 0 AF XY: 0.000612 AC XY: 83 AN XY: 135608

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000885

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00111 AC: 1619 AN: 1461474 Hom.: 3 Cov.: 32 AF XY: 0.00109 AC XY: 789 AN XY: 727074

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.000301

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74474

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.000536

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.000545

EpiControl AF: 0.000948

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.47	N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.092
Sift	Benign	0.18	T
Sift4G	Benign	1.0	T
Polyphen		0.63	P
Vest4		0.16
MVP		0.30
MPC		0.25
ClinPred		0.018	T
GERP RS		2.6
Varity_R		0.043
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs147638897; hg19: chr8-134232950;