rs2280153

Variant names:

• chr6-112054441-G-A
• rs2280153
• NM_198239.2:c.48+36G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198239.2(CCN6):​c.48+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,601,226 control chromosomes in the GnomAD database, including 52,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4688 hom., cov: 30)
  • Exomes 𝑓: 0.25 (48275 hom.)
• Consequence: CCN6 NM_198239.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-112054441-G-A is Benign according to our data. Variant chr6-112054441-G-A is described in ClinVar as Benign. ClinVar VariationId is 1264724.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN6	NM_198239.2	MANE Select	c.48+36G>A		intron	N/A	NP_937882.2	A0A384NYW3
	CCN6	NM_003880.4		c.48+36G>A		intron	N/A	NP_003871.1	A0A384NYW3
	CCN6	NR_125353.2		n.302+36G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN6	ENST00000368666.7	TSL:1 MANE Select	c.48+36G>A		intron	N/A	ENSP00000357655.4	O95389-1
	CCN6	ENST00000230529.9	TSL:5	c.48+36G>A		intron	N/A	ENSP00000230529.5	O95389-1
	CCN6	ENST00000604763.5	TSL:5	c.48+36G>A		intron	N/A	ENSP00000473777.1	O95389-1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37535 AN: 151474 Hom.: 4689 Cov.: 30

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.234 AC: 58490 AN: 249780 AF XY: 0.231

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.329

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.254 AC: 368788 AN: 1449634 Hom.: 48275 Cov.: 27 AF XY: 0.251 AC XY: 181010 AN XY: 721958

African (AFR) AF: 0.247 AC: 8202 AN: 33200

American (AMR) AF: 0.188 AC: 8397 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7619 AN: 26070

East Asian (EAS) AF: 0.309 AC: 12234 AN: 39626

South Asian (SAS) AF: 0.135 AC: 11572 AN: 85984

European-Finnish (FIN) AF: 0.202 AC: 10639 AN: 52664

Middle Eastern (MID) AF: 0.216 AC: 1241 AN: 5738

European-Non Finnish (NFE) AF: 0.267 AC: 293737 AN: 1101648

Other (OTH) AF: 0.252 AC: 15147 AN: 59994

GnomAD4 genome AF: 0.248 AC: 37548 AN: 151592 Hom.: 4688 Cov.: 30 AF XY: 0.242 AC XY: 17926 AN XY: 74070

African (AFR) AF: 0.249 AC: 10274 AN: 41272

American (AMR) AF: 0.209 AC: 3190 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1040 AN: 3468

East Asian (EAS) AF: 0.321 AC: 1641 AN: 5110

South Asian (SAS) AF: 0.139 AC: 667 AN: 4794

European-Finnish (FIN) AF: 0.189 AC: 1995 AN: 10536

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17923 AN: 67878

Other (OTH) AF: 0.264 AC: 556 AN: 2104

Alfa AF: 0.259 Hom.: 1178

Bravo AF: 0.252

Asia WGS AF: 0.230 AC: 799 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.46
DANN	Benign	0.56
PhyloP100		-1.3
PromoterAI		0.0058	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2280153; hg19: chr6-112375644;