6-112054634-G-A

Position:

• chr6-112054634-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198239.2(CCN6):​c.48+229G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.008 in 541,248 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (21 hom.)
• Consequence: CCN6 NM_198239.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.77

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=-0.89).
• BP6: Variant 6-112054634-G-A is Benign according to our data. Variant chr6-112054634-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1335640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00719 (1095/152190) while in subpopulation NFE AF= 0.00985 (670/68004). AF 95% confidence interval is 0.00923. There are 6 homozygotes in gnomad4. There are 517 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCN6	NM_198239.2	c.48+229G>A		intron_variant		ENST00000368666.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCN6	ENST00000368666.7	c.48+229G>A		intron_variant		1	NM_198239.2	P1

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1094 AN: 152072 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00985

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.00832 AC: 3237 AN: 389058 Hom.: 21 Cov.: 3 AF XY: 0.00816 AC XY: 1705 AN XY: 208890

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.00608

Gnomad4 ASJ exome AF: 0.00995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000659

Gnomad4 FIN exome AF: 0.0205

Gnomad4 NFE exome AF: 0.00998

Gnomad4 OTH exome AF: 0.00864

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152190 Hom.: 6 Cov.: 32 AF XY: 0.00695 AC XY: 517 AN XY: 74382

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.00985

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0100 Hom.: 1

Bravo AF: 0.00659

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CCN6: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.53
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs76664940; hg19: chr6-112375837;