rs781838640
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_198239.2(CCN6):βc.868_869delβ(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 (β β ). Synonymous variant affecting the same amino acid position (i.e. Q289Q) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000062 ( 0 hom. )
Consequence
CCN6
NM_198239.2 frameshift
NM_198239.2 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251034Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135686
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461414Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727010
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at