rs121908902

Positions:

• chr6-112061174-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000368666.7(CCN6):​c.232T>C​(p.Cys78Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C78Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCN6 ENST00000368666.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90

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 11 ACMG points.

• PM1: In a disulfide_bond (size 17) in uniprot entity CCN6_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in ENST00000368666.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-112061175-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 631969.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 6-112061174-T-C is Pathogenic according to our data. Variant chr6-112061174-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6382.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-112061174-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN6	NM_198239.2	c.232T>C	p.Cys78Arg	missense_variant	2/5	ENST00000368666.7	NP_937882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCN6	ENST00000368666.7	c.232T>C	p.Cys78Arg	missense_variant	2/5	1	NM_198239.2	ENSP00000357655	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive pseudorheumatoid dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T;T;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.;.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	.;H;H;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-11	.;D;.;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0080	.;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.96
MutPred		0.98		.;Loss of ubiquitination at K76 (P = 0.051);Loss of ubiquitination at K76 (P = 0.051);Loss of ubiquitination at K76 (P = 0.051);.;
MVP		0.99
MPC		0.48
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.94

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: rs121908902; hg19: chr6-112382377;