Genetic Variant CCN3:p.Cys15Phe (chr8-119416576-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002514.4(CCN3):c.44G>T(p.Cys15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,614,040 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 11 hom. )

Consequence

CCN3
NM_002514.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.560

Publications

0 publications found

Variant links:

Genes affected

CCN3 (HGNC:7885): (cellular communication network factor 3) The protein encoded by this gene is a small secreted cysteine-rich protein and a member of the CCN family of regulatory proteins. CNN family proteins associate with the extracellular matrix and play an important role in cardiovascular and skeletal development, fibrosis and cancer development. [provided by RefSeq, Feb 2009]

CCN3 links:

ENSG00000286282 (HGNC:):

ENSG00000286282 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003968537).

BP6

Variant 8-119416576-G-T is Benign according to our data. Variant chr8-119416576-G-T is described in ClinVar as Benign. ClinVar VariationId is 775267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00635 (967/152360) while in subpopulation AFR AF = 0.0175 (727/41586). AF 95% confidence interval is 0.0164. There are 7 homozygotes in GnomAd4. There are 462 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002514.4. 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
	CCN3	NM_002514.4	MANE Select	c.44G>T	p.Cys15Phe	missense	Exon 1 of 5	NP_002505.1	P48745

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCN3	ENST00000259526.4	TSL:1 MANE Select	c.44G>T	p.Cys15Phe	missense	Exon 1 of 5	ENSP00000259526.3	P48745
CCN3	ENST00000864983.1		c.44G>T	p.Cys15Phe	missense	Exon 1 of 5	ENSP00000535042.1
CCN3	ENST00000960553.1		c.44G>T	p.Cys15Phe	missense	Exon 1 of 4	ENSP00000630612.1

Frequencies

GnomAD3 genomes

AF:

0.00634

AC:

965

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00334

AC:

836

AN:

250006

AF XY:

0.00272

show subpopulations

Gnomad AFR exome

AF:

0.0192

Gnomad AMR exome

AF:

0.00394

Gnomad ASJ exome

AF:

0.0232

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00170

AC:

2482

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1226

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.0168

AC:

563

AN:

33478

American (AMR)

AF:

0.00374

AC:

167

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

660

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000732

AC:

814

AN:

1111942

Other (OTH)

AF:

0.00391

AC:

236

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

144

288

433

577

721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00635

AC:

967

AN:

152360

Hom.:

Cov.:

AF XY:

0.00620

AC XY:

462

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0175

AC:

727

AN:

41586

American (AMR)

AF:

0.00444

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68034

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00357

Hom.:

Bravo

AF:

0.00713

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00335

AC:

407

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00184

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.91

PhyloP100

0.56

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.2

REVEL

Benign

0.22

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.010

Vest4

0.37

MVP

0.70

MPC

0.39

ClinPred

0.029

GERP RS

3.5

PromoterAI

0.040

Neutral

(source)

gMVP

0.51

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over