chr6-112054634-G-A

Variant names:

• chr6-112054634-G-A
• rs76664940
• NM_198239.2:c.48+229G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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=-0.89).
• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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+229G>A		intron	N/A	NP_937882.2	A0A384NYW3
	CCN6	NM_003880.4		c.48+229G>A		intron	N/A	NP_003871.1	A0A384NYW3
	CCN6	NR_125353.2		n.302+229G>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+229G>A		intron	N/A	ENSP00000357655.4	O95389-1
	CCN6	ENST00000483439.1	TSL:3	c.60G>A	p.Pro20Pro	synonymous	Exon 2 of 2	ENSP00000501523.1	A0A6I8PRG4
	CCN6	ENST00000674325.1		c.60G>A	p.Pro20Pro	synonymous	Exon 3 of 3	ENSP00000501404.1	A0A6I8PRG4

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

African (AFR) AF: 0.00127 AC: 14 AN: 11058

American (AMR) AF: 0.00608 AC: 112 AN: 18430

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 116 AN: 11660

East Asian (EAS) AF: 0.00 AC: 0 AN: 24410

South Asian (SAS) AF: 0.000659 AC: 30 AN: 45496

European-Finnish (FIN) AF: 0.0205 AC: 452 AN: 22066

Middle Eastern (MID) AF: 0.00303 AC: 5 AN: 1652

European-Non Finnish (NFE) AF: 0.00998 AC: 2319 AN: 232420

Other (OTH) AF: 0.00864 AC: 189 AN: 21866

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

African (AFR) AF: 0.00171 AC: 71 AN: 41504

American (AMR) AF: 0.00797 AC: 122 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00985 AC: 670 AN: 68004

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0100 Hom.: 1

Bravo AF: 0.00659

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.53
DANN	Benign	0.69
PhyloP100		-1.8
PromoterAI		-0.046	Neutral
Mutation Taster		=100/0	polymorphism

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: rs76664940; hg19: chr6-112375837;