Variant 8-119416552-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002514.4(CCN3):c.20C>A(p.Thr7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

CCN3
NM_002514.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.209

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:

CCN3 (HGNC:):

CCN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN3	NM_002514.4 linkuse as main transcript	c.20C>A	p.Thr7Lys	missense_variant	1/5	ENST00000259526.4	NP_002505.1	P48745A0A024R9J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CCN3	ENST00000259526.4 linkuse as main transcript	c.20C>A	p.Thr7Lys	missense_variant	1/5	1	NM_002514.4	ENSP00000259526.3	P48745
CCN3	ENST00000520082.1 linkuse as main transcript	n.103C>A		non_coding_transcript_exon_variant	1/2	2
ENSG00000286282	ENST00000670132.1 linkuse as main transcript	n.264+132G>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

250668

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000272

AC:

397

AN:

1461648

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

184

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000328

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000118

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000520

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2024

The c.20C>A (p.T7K) alteration is located in exon 1 (coding exon 1) of the NOV gene. This alteration results from a C to A substitution at nucleotide position 20, causing the threonine (T) at amino acid position 7 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.48

CADD

Benign

1.0

DANN

Benign

0.89

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.40

M_CAP

Benign

0.039

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.86

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.85

REVEL

Benign

0.28

Sift

Benign

0.16

Sift4G

Benign

0.40

Vest4

0.19

MVP

0.42

MPC

0.27

ClinPred

0.031

GERP RS

-2.6

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over