6-131950080-C-G

Variant names:

• chr6-131950080-C-G
• rs187658120
• NM_001901.4:c.622G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001901.4(CCN2):​c.622G>C​(p.Ala208Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A208T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCN2 NM_001901.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 4 publications found

Genes affected

CCN2 (HGNC:2500): (cellular communication network factor 2) The protein encoded by this gene is a mitogen that is secreted by vascular endothelial cells. The encoded protein plays a role in chondrocyte proliferation and differentiation, cell adhesion in many cell types, and is related to platelet-derived growth factor. Certain polymorphisms in this gene have been linked with a higher incidence of systemic sclerosis. [provided by RefSeq, Nov 2009]

LINC01013 (HGNC:48987): (long intergenic non-protein coding RNA 1013)

CCN2-AS1 (HGNC:40164): (CCN2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001901.4. 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
	CCN2	NM_001901.4	MANE Select	c.622G>C	p.Ala208Pro	missense	Exon 4 of 5	NP_001892.2	P29279-1
	CCN2-AS1	NR_187593.1		n.371+39125C>G		intron	N/A
	CCN2-AS1	NR_187594.1		n.488+45846C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN2	ENST00000367976.4	TSL:1 MANE Select	c.622G>C	p.Ala208Pro	missense	Exon 4 of 5	ENSP00000356954.3	P29279-1
	CCN2	ENST00000873798.1		c.622G>C	p.Ala208Pro	missense	Exon 4 of 5	ENSP00000543857.1
	CCN2	ENST00000918595.1		c.616G>C	p.Ala206Pro	missense	Exon 4 of 5	ENSP00000588654.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.20	N
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.40
Sift	Benign	0.19	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.61		Gain of disorder (P = 0.0662)
MVP		0.67
MPC		0.96
ClinPred		0.85	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.80
Mutation Taster		=24/76	disease causing

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: rs187658120; hg19: chr6-132271220;