rs781838640

chr6-112069420-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_198239.2(CCN6):c.868_869del(p.Ser290LeufsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000616 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q289Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CCN6 NM_198239.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.59

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-112069420-CAG-C is Pathogenic according to our data. Variant chr6-112069420-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 453263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112069420-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN6	NM_198239.2	c.868_869del	p.Ser290LeufsTer12	frameshift_variant	5/5	ENST00000368666.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN6	ENST00000368666.7	c.868_869del	p.Ser290LeufsTer12	frameshift_variant	5/5	1	NM_198239.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251034 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461414 Hom.: 0 AF XY: 0.00000825 AC XY: 6 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive pseudorheumatoid dysplasia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1999	- -
Pathogenic, criteria provided, single submitter	research	Cirak Lab, University Hospital Cologne	Dec 08, 2017	It is a known disease causing mutation in homozygous state, the phenotype fits to the mutation. It is frameshifting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change creates a premature translational stop signal (p.Ser290Leufs*12) in the WISP3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 65 amino acid(s) of the WISP3 protein. This variant is present in population databases (rs781838640, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with progressive pseudorheumatoid dysplasia (PMID: 10471507, 22791401, 29258992). This variant is also known as 866delAG. ClinVar contains an entry for this variant (Variation ID: 453263). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs781838640; hg19: chr6-112390623;