NM_198239.2:c.-254A>G

Variant names:

• chr6-112054104-A-G
• rs3806964
• NM_198239.2:c.-254A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.-254A>G		5_prime_UTR	Exon 1 of 5	NP_937882.2	A0A384NYW3
	CCN6	NM_003880.4		c.-81A>G		5_prime_UTR	Exon 1 of 6	NP_003871.1	A0A384NYW3
	CCN6	NR_125353.2		n.1A>G		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN6	ENST00000368666.7	TSL:1 MANE Select	c.-254A>G		5_prime_UTR	Exon 1 of 5	ENSP00000357655.4	O95389-1
	CCN6	ENST00000230529.9	TSL:5	c.-81A>G		5_prime_UTR	Exon 1 of 6	ENSP00000230529.5	O95389-1
	CCN6	ENST00000604763.5	TSL:5	c.-90A>G		5_prime_UTR	Exon 1 of 6	ENSP00000473777.1	O95389-1

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

African (AFR) AF: 0.248 AC: 3605 AN: 14514

American (AMR) AF: 0.195 AC: 6008 AN: 30772

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 4769 AN: 15972

East Asian (EAS) AF: 0.305 AC: 9360 AN: 30734

South Asian (SAS) AF: 0.138 AC: 7338 AN: 53086

European-Finnish (FIN) AF: 0.219 AC: 7848 AN: 35884

Middle Eastern (MID) AF: 0.242 AC: 522 AN: 2158

European-Non Finnish (NFE) AF: 0.269 AC: 76983 AN: 286136

Other (OTH) AF: 0.258 AC: 7121 AN: 27622

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

African (AFR) AF: 0.252 AC: 10445 AN: 41428

American (AMR) AF: 0.212 AC: 3246 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1053 AN: 3464

East Asian (EAS) AF: 0.321 AC: 1649 AN: 5138

South Asian (SAS) AF: 0.144 AC: 688 AN: 4790

European-Finnish (FIN) AF: 0.207 AC: 2194 AN: 10574

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

European-Non Finnish (NFE) AF: 0.269 AC: 18311 AN: 67948

Other (OTH) AF: 0.267 AC: 563 AN: 2106

Alfa AF: 0.262 Hom.: 2963

Bravo AF: 0.257

Asia WGS AF: 0.232 AC: 805 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Progressive pseudorheumatoid dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.6
DANN	Benign	0.36
PhyloP100		-3.3
PromoterAI		0.0022	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

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