rs1230345

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.168G>T(p.Gln56His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,613,864 control chromosomes in the GnomAD database, including 63,175 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8092 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55083 hom. )

Consequence

CCN6
NM_198239.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.03

Publications

41 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:

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=1.9323826E-4).

BP6

Variant 6-112061110-G-T is Benign according to our data. Variant chr6-112061110-G-T is described in ClinVar as Benign. ClinVar VariationId is 355060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

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.168G>T	p.Gln56His	missense	Exon 2 of 5	NP_937882.2	A0A384NYW3
CCN6	NM_003880.4		c.168G>T	p.Gln56His	missense	Exon 3 of 6	NP_003871.1	A0A384NYW3
CCN6	NR_125353.2		n.422G>T		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCN6	ENST00000368666.7	TSL:1 MANE Select	c.168G>T	p.Gln56His	missense	Exon 2 of 5	ENSP00000357655.4	O95389-1
CCN6	ENST00000620524.3	TSL:1	n.102G>T		non_coding_transcript_exon	Exon 2 of 5
CCN6	ENST00000230529.9	TSL:5	c.168G>T	p.Gln56His	missense	Exon 3 of 6	ENSP00000230529.5	O95389-1

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

47568

AN:

151872

Hom.:

8074

Cov.:

show subpopulations

Gnomad AFR

AF:

0.456

Gnomad AMI

AF:

0.215

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.308

GnomAD2 exomes

AF:

0.256

AC:

64353

AN:

251302

AF XY:

0.249

show subpopulations

Gnomad AFR exome

AF:

0.464

Gnomad AMR exome

AF:

0.192

Gnomad ASJ exome

AF:

0.303

Gnomad EAS exome

AF:

0.319

Gnomad FIN exome

AF:

0.211

Gnomad NFE exome

AF:

0.272

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.270

AC:

394417

AN:

1461874

Hom.:

55083

Cov.:

AF XY:

0.265

AC XY:

192746

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.464

AC:

15540

AN:

33480

American (AMR)

AF:

0.200

AC:

8950

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

7848

AN:

26136

East Asian (EAS)

AF:

0.299

AC:

11856

AN:

39700

South Asian (SAS)

AF:

0.139

AC:

11979

AN:

86258

European-Finnish (FIN)

AF:

0.217

AC:

11618

AN:

53420

Middle Eastern (MID)

AF:

0.234

AC:

1351

AN:

5768

European-Non Finnish (NFE)

AF:

0.278

AC:

308692

AN:

1112000

Other (OTH)

AF:

0.275

AC:

16583

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

20652

41304

61957

82609

103261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10362

20724

31086

41448

51810

<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:

0.313

AC:

47628

AN:

151990

Hom.:

8092

Cov.:

AF XY:

0.306

AC XY:

22726

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.456

AC:

18895

AN:

41428

American (AMR)

AF:

0.231

AC:

3536

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1066

AN:

3466

East Asian (EAS)

AF:

0.309

AC:

1597

AN:

5162

South Asian (SAS)

AF:

0.146

AC:

704

AN:

4812

European-Finnish (FIN)

AF:

0.209

AC:

2205

AN:

10566

Middle Eastern (MID)

AF:

0.264

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.275

AC:

18703

AN:

67964

Other (OTH)

AF:

0.308

AC:

649

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1585

3170

4754

6339

7924

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<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:

0.286

Hom.:

24968

Bravo

AF:

0.324

TwinsUK

AF:

0.273

AC:

1012

ALSPAC

AF:

0.270

AC:

1042

ESP6500AA

AF:

0.452

AC:

1991

ESP6500EA

AF:

0.277

AC:

2381

ExAC

AF:

0.261

AC:

31635

Asia WGS

AF:

0.248

AC:

860

AN:

3478

EpiCase

AF:

0.279

EpiControl

AF:

0.280

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Progressive pseudorheumatoid dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.2

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.057

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.0041

MetaRNN

Benign

0.00019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

PhyloP100

-1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.0

REVEL

Benign

0.039

Sift

Benign

0.26

Sift4G

Benign

0.15

Polyphen

0.0

Vest4

0.048

MutPred

0.15

Loss of solvent accessibility (P = 0.001)

MPC

0.056

ClinPred

0.0032

GERP RS

-7.3

Varity_R

0.059

gMVP

0.29

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over