rs781986930

chr6-112069565-G-Achr6-112069565-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_198239.2(CCN6):c.1010G>A(p.Cys337Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CCN6 NM_198239.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.84

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 16 ACMG points.

• PM1: In a disulfide_bond (size 38) in uniprot entity CCN6_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_198239.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 6-112069565-G-A is Pathogenic according to our data. Variant chr6-112069565-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112069565-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN6	NM_198239.2	c.1010G>A	p.Cys337Tyr	missense_variant	5/5	ENST00000368666.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN6	ENST00000368666.7	c.1010G>A	p.Cys337Tyr	missense_variant	5/5	1	NM_198239.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251082 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135692

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: 0.0000185 AC: 27 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727038

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive pseudorheumatoid dysplasia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The missense c.1010G>A(p.Cys337Tyr) variant in CCN6 gene has been reported in homozygous state in multiple individuals affected with Progressive pseudorheumatoid dysplasia (Madhuri V, et. al., 2016; Dalal A, et. al.,2012). The p.Cys337Tyr variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Cys337Tyr in CCN6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 337 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Feb 27, 2019	This variant is interpreted as a Pathogenic for Progressive pseudorheumatoid arthropathy of childhood, autosomal recessive. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1-Moderate : PP1 upgraded in strength to Moderate (PMID:22987568). PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Very strong : PM3 upgraded in strength to Very Strong to account for multiple jnrelated homozygous and compound heterozygous probands (PMID:22987568; 27436824; 25988854). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	May 09, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 337 of the WISP3 protein (p.Cys337Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with progressive pseudorheumatoid dysplasia (PMID: 22791401, 22987568, 23270760, 25988854, 32351055). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1064G>A or C337T. ClinVar contains an entry for this variant (Variation ID: 521955). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;.;D;.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
REVEL	Pathogenic	0.96
Sift4G	Pathogenic	0.0	D;D;D;D;D;.
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.95
MutPred		0.89		.;Gain of MoRF binding (P = 0.1238);Gain of MoRF binding (P = 0.1238);.;Gain of MoRF binding (P = 0.1238);.;
MVP		1.0
MPC		0.47
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.97

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: rs781986930; hg19: chr6-112390768; COSMIC: COSV57888434; COSMIC: COSV57888434;