chr6-112069555-T-C

Position:

• chr6-112069555-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_198239.2(CCN6):​c.1000T>C​(p.Ser334Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCN6 NM_198239.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.11

Genes affected

CCN6 (HGNC:12771): (cellular communication network factor 6) 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 is overexpressed in colon tumors. It may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. Mutations of this gene are associated with progressive pseudorheumatoid dysplasia, an autosomal recessive skeletal disorder, indicating that the gene is essential for normal postnatal skeletal growth and cartilage homeostasis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CCN6 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 6-112069555-T-C is Pathogenic according to our data. Variant chr6-112069555-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6388.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN6	NM_198239.2	c.1000T>C	p.Ser334Pro	missense_variant	5/5	ENST00000368666.7	NP_937882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCN6	ENST00000368666.7	c.1000T>C	p.Ser334Pro	missense_variant	5/5	1	NM_198239.2	ENSP00000357655.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2023

This missense change has been observed in individual(s) with progressive pseudorheumatoid dysplasia (PMID: 15631777, 22685593). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 334 of the WISP3 protein (p.Ser334Pro). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 6388). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WISP3 protein function. For these reasons, this variant has been classified as Pathogenic. -

Progressive pseudorheumatoid dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;D;.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	D;D;.;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.0	.;M;M;.;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	.;D;.;D;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0060	.;D;.;D;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;.
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.84
MutPred		0.91		.;Loss of MoRF binding (P = 0.0745);Loss of MoRF binding (P = 0.0745);.;Loss of MoRF binding (P = 0.0745);.;
MVP		0.98
MPC		0.41
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.95

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: rs121908903; hg19: chr6-112390758;