6-112054104-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198239.2(CCN6):c.-254A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 648,812 control chromosomes in the GnomAD database, including 21,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4905 hom., cov: 31)
  • Exomes 𝑓: 0.25 (16274 hom.)
• Consequence: CCN6 NM_198239.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.34

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-112054104-A-G is Benign according to our data. Variant chr6-112054104-A-G is described in ClinVar as [Benign]. Clinvar id is 355054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN6	NM_198239.2	c.-254A>G		5_prime_UTR_variant	1/5	ENST00000368666.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN6	ENST00000368666.7	c.-254A>G		5_prime_UTR_variant	1/5	1	NM_198239.2	P1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38402 AN: 151818 Hom.: 4905 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.249 AC: 123554 AN: 496878 Hom.: 16274 Cov.: 4 AF XY: 0.243 AC XY: 64401 AN XY: 265460

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.253 AC: 38416 AN: 151934 Hom.: 4905 Cov.: 31 AF XY: 0.248 AC XY: 18405 AN XY: 74242

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.267

Alfa AF: 0.259 Hom.: 1777

Bravo AF: 0.257

Asia WGS AF: 0.232 AC: 805 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Progressive pseudorheumatoid dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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
BayesDel_noAF	Benign	-0.90
Cadd	Benign	4.6
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs3806964; hg19: chr6-112375307; COSMIC: COSV57890754; COSMIC: COSV57890754;