8-119416950-C-A

Position:

chr8-119416950-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The NM_002514.4(CCN3):c.291C>A(p.Asn97Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,612,768 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

CCN3
NM_002514.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.328

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 -1 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity CCN3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.004511416).

BP6

Variant 8-119416950-C-A is Benign according to our data. Variant chr8-119416950-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 721280.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN3	NM_002514.4 linkuse as main transcript	c.291C>A	p.Asn97Lys	missense_variant	2/5	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.291C>A	p.Asn97Lys	missense_variant	2/5	1	NM_002514.4	ENSP00000259526.3	P48745
CCN3	ENST00000520082.1 linkuse as main transcript	n.374C>A		non_coding_transcript_exon_variant	2/2	2
ENSG00000286282	ENST00000670132.1 linkuse as main transcript	n.-3G>T		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000616

AC:

153

AN:

248436

Hom.:

AF XY:

0.000565

AC XY:

AN XY:

134582

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00331

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000950

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.000521

AC:

761

AN:

1460430

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

378

AN XY:

726314

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00353

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000552

Gnomad4 OTH exome

AF:

0.000531

GnomAD4 genome

AF:

0.000512

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000966

Hom.:

Bravo

AF:

0.000518

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000982

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.291C>A (p.N97K) alteration is located in exon 2 (coding exon 2) of the NOV gene. This alteration results from a C to A substitution at nucleotide position 291, causing the asparagine (N) at amino acid position 97 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.90

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.61

M_CAP

Benign

0.014

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.45

PROVEAN

Benign

0.30

REVEL

Benign

0.046

Sift

Benign

0.95

Sift4G

Benign

0.98

Vest4

0.073

MutPred

0.46

Gain of methylation at N97 (P = 0.0051);

MVP

0.20

MPC

0.26

ClinPred

0.0041

GERP RS

1.1

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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