6-112061110-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 355060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112061110-G-T is described in Lovd as [Benign]. Variant chr6-112061110-G-T is described in Lovd as [Likely_benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN6	NM_198239.2 link	c.168G>T	p.Gln56His	missense_variant	Exon 2 of 5	ENST00000368666.7	NP_937882.2	O95389-1A0A384NYW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN6	ENST00000368666.7 link	c.168G>T	p.Gln56His	missense_variant	Exon 2 of 5	1	NM_198239.2	ENSP00000357655.4		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

GnomAD3 exomes

AF:

0.256

AC:

64353

AN:

251302

Hom.:

9132

AF XY:

0.249

AC XY:

33806

AN XY:

135826

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 SAS exome

AF:

0.135

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

Gnomad4 AFR exome

AF:

0.464

Gnomad4 AMR exome

AF:

0.200

Gnomad4 ASJ exome

AF:

0.300

Gnomad4 EAS exome

AF:

0.299

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.217

Gnomad4 NFE exome

AF:

0.278

Gnomad4 OTH exome

AF:

0.275

GnomAD4 genome

AF:

0.313

AC:

47628

AN:

151990

Hom.:

8092

Cov.:

AF XY:

0.306

AC XY:

22726

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.456

Gnomad4 AMR

AF:

0.231

Gnomad4 ASJ

AF:

0.308

Gnomad4 EAS

AF:

0.309

Gnomad4 SAS

AF:

0.146

Gnomad4 FIN

AF:

0.209

Gnomad4 NFE

AF:

0.275

Gnomad4 OTH

AF:

0.308

Alfa

AF:

0.284

Hom.:

12436

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive pseudorheumatoid dysplasia

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.2

DANN

Benign

0.60

DEOGEN2

Benign

0.057

.;T;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.0041

T;T;.;.;T

MetaRNN

Benign

0.00019

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

.;N;N;N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.0

.;N;.;.;.

REVEL

Benign

0.039

Sift

Benign

0.26

.;T;.;.;.

Sift4G

Benign

0.15

T;T;T;T;.

Polyphen

0.0

B;B;B;B;.

Vest4

0.048

MutPred

0.15

.;Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);.;

MPC

0.056

ClinPred

0.0032

GERP RS

-7.3

Varity_R

0.059

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over