6-112061120-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198239.2(CCN6):c.178C>T(p.Arg60Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,614,098 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R60H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.028 ( 199 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 193 hom. )

Consequence

CCN6
NM_198239.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0430

Publications

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

CCN6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004796684).

BP6

Variant 6-112061120-C-T is Benign according to our data. Variant chr6-112061120-C-T is described in ClinVar as Benign. ClinVar VariationId is 355061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN6	NM_198239.2 link	c.178C>T	p.Arg60Cys	missense_variant	Exon 2 of 5	ENST00000368666.7	NP_937882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN6	ENST00000368666.7 link	c.178C>T	p.Arg60Cys	missense_variant	Exon 2 of 5	1	NM_198239.2	ENSP00000357655.4

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4288

AN:

152098

Hom.:

198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0994

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.00747

AC:

1878

AN:

251338

AF XY:

0.00548

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00289

AC:

4226

AN:

1461882

Hom.:

193

Cov.:

AF XY:

0.00250

AC XY:

1815

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.102

AC:

3406

AN:

33480

American (AMR)

AF:

0.00429

AC:

192

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00333

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00537

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000125

AC:

139

AN:

1112010

Other (OTH)

AF:

0.00588

AC:

355

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

257

514

772

1029

1286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0282

AC:

4298

AN:

152216

Hom.:

199

Cov.:

AF XY:

0.0275

AC XY:

2044

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0993

AC:

4123

AN:

41506

American (AMR)

AF:

0.00693

AC:

106

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68022

Other (OTH)

AF:

0.0161

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

201

402

602

803

1004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00997

Hom.:

160

Bravo

AF:

0.0310

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.100

AC:

441

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00937

AC:

1138

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 06, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive pseudorheumatoid dysplasia

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 31, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.32

.;T;T;T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.062

LIST_S2

Uncertain

0.91

D;D;.;.;D

MetaRNN

Benign

0.0048

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;M;M;M;.

PhyloP100

-0.043

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.2

.;D;.;.;.

REVEL

Benign

0.096

Sift

Benign

0.034

.;D;.;.;.

Sift4G

Benign

0.16

T;T;T;T;.

Polyphen

0.77

P;B;B;B;.

Vest4

0.19

MVP

0.56

MPC

0.22

ClinPred

0.042

GERP RS

2.3

Varity_R

0.29

gMVP

0.37

Mutation Taster

=99/1

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over