Genetic Variant CCN6:p.Leu14Pro (chr6-112054398-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_198239.2(CCN6):c.41T>C(p.Leu14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

CCN6
NM_198239.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Publications

0 publications found

Variant links:

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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

CCN6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3214323).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198239.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCN6	NM_198239.2	MANE Select	c.41T>C	p.Leu14Pro	missense	Exon 1 of 5	NP_937882.2	A0A384NYW3
CCN6	NM_003880.4		c.41T>C	p.Leu14Pro	missense	Exon 2 of 6	NP_003871.1	A0A384NYW3
CCN6	NR_125353.2		n.295T>C		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCN6	ENST00000368666.7	TSL:1 MANE Select	c.41T>C	p.Leu14Pro	missense	Exon 1 of 5	ENSP00000357655.4	O95389-1
CCN6	ENST00000230529.9	TSL:5	c.41T>C	p.Leu14Pro	missense	Exon 2 of 6	ENSP00000230529.5	O95389-1
CCN6	ENST00000604763.5	TSL:5	c.41T>C	p.Leu14Pro	missense	Exon 2 of 6	ENSP00000473777.1	O95389-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251302

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.57

M_CAP

Benign

0.077

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.69

PhyloP100

1.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.52

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.033

Polyphen

0.90

Vest4

0.39

MVP

0.58

MPC

0.44

ClinPred

0.52

GERP RS

2.6

PromoterAI

0.034

Neutral

(source)

Varity_R

0.37

gMVP

0.38

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over