rs797044439

Positions:

• chr6-112054406-G-GT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_198239.2(CCN6):​c.48+2dup variant causes a splice donor change. The variant allele was found at a frequency of 0.00000137 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCN6 NM_198239.2 splice_donor
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.35

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2826291 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.6, offset of 0 (no position change), new splice context is: cagGTtaag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-112054406-G-GT is Pathogenic according to our data. Variant chr6-112054406-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 6384.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN6	NM_198239.2	c.48+2dup		splice_donor_variant		ENST00000368666.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN6	ENST00000368666.7	c.48+2dup		splice_donor_variant		1	NM_198239.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive pseudorheumatoid dysplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Nov 09, 2019	In-silico splice prediction tool (NNSPLICE) suggest that this variant might affect splicing due to the loss of constitutive splice site, which in turn might lead to a frameshift and consequent premature termination of the protein; this will likely result in loss-of-function. The variant (reported as insT+2IVS1) has been previously reported in a family from Jordan with progressive pseudorheumatoid arthropathy of childhood in homozygous state and it was not detected in the studied controls [PMID: 10471507] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1999	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797044439; hg19: chr6-112375609;