8-133220665-C-T

Position:

• chr8-133220665-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003882.4(CCN4):​c.434C>T​(p.Thr145Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,614,136 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: CCN4 NM_003882.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.55

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052740157).
• BP6: Variant 8-133220665-C-T is Benign according to our data. Variant chr8-133220665-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 721056.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN4	NM_003882.4	c.434C>T	p.Thr145Met	missense_variant	3/5	ENST00000250160.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN4	ENST00000250160.11	c.434C>T	p.Thr145Met	missense_variant	3/5	1	NM_003882.4	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152244 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00149 AC: 374 AN: 251104 Hom.: 0 AF XY: 0.00161 AC XY: 219 AN XY: 135832

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00212 AC: 3094 AN: 1461774 Hom.: 5 Cov.: 32 AF XY: 0.00215 AC XY: 1566 AN XY: 727208

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00253

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00242

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152362 Hom.: 2 Cov.: 33 AF XY: 0.00129 AC XY: 96 AN XY: 74518

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00209 Hom.: 3

Bravo AF: 0.00138

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00207

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.053	T
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.48
Sift	Benign	0.14	T
Sift4G	Benign	0.26	T
Polyphen		0.99	D
Vest4		0.61
MVP		0.86
MPC		0.51
ClinPred		0.026	T
GERP RS		4.6
Varity_R		0.067
gMVP		0.50

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: rs139669488; hg19: chr8-134232908; COSMIC: COSV51532531;