rs121908903

Variant names:

• chr6-112069555-T-A
• rs121908903
• NM_198239.2:c.1000T>A

Your query was ambiguous. Multiple possible variants found:

• chr6-112069555-T-A
• chr6-112069555-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_198239.2(CCN6):​c.1000T>A​(p.Ser334Thr) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S334P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCN6 NM_198239.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.11
• Publications: 0 publications found

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]

CCN6 Gene-Disease associations (from GenCC):

• progressive pseudorheumatoid arthropathy of childhood

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-112069555-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 6388.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN6	NM_198239.2	c.1000T>A	p.Ser334Thr	missense_variant	Exon 5 of 5	ENST00000368666.7	NP_937882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN6	ENST00000368666.7	c.1000T>A	p.Ser334Thr	missense_variant	Exon 5 of 5	1	NM_198239.2	ENSP00000357655.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ser334 amino acid residue in WISP3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15631777, 22685593). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with WISP3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with threonine at codon 334 of the WISP3 protein (p.Ser334Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Benign	0.86
DEOGEN2	Uncertain	0.42	.;T;T;.;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;T;.;D;.;T
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.4	.;L;L;.;L;.
PhyloP100		6.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	.;N;.;N;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.76	.;T;.;T;.;.
Sift4G	Benign	0.29	T;T;T;D;T;.
Polyphen		0.98	D;D;D;.;D;.
Vest4		0.57
MutPred		0.81		.;Loss of catalytic residue at S334 (P = 0.1548);Loss of catalytic residue at S334 (P = 0.1548);.;Loss of catalytic residue at S334 (P = 0.1548);.;
MVP		0.88
MPC		0.36
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.34
gMVP		0.68
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs121908903; hg19: chr6-112390758;