Genetic Variant CSPG5:p.Arg458Cys (chr3-47572696-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006574.4(CSPG5):c.1372C>T(p.Arg458Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

CSPG5
NM_006574.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.22

Variant links:

Genes affected

CSPG5 (HGNC:2467): (chondroitin sulfate proteoglycan 5) The protein encoded by this gene is a proteoglycan that may function as a neural growth and differentiation factor. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

CSPG5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSPG5	NM_006574.4 link	c.1372C>T	p.Arg458Cys	missense_variant	Exon 3 of 5	ENST00000264723.9	NP_006565.2	O95196-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CSPG5	ENST00000264723.9 link	c.1372C>T	p.Arg458Cys	missense_variant	Exon 3 of 5	1	NM_006574.4	ENSP00000264723.4	O95196-2
CSPG5	ENST00000383738.6 link	c.1372C>T	p.Arg458Cys	missense_variant	Exon 3 of 5	1		ENSP00000373244.2	O95196-1
CSPG5	ENST00000456150.5 link	c.958C>T	p.Arg320Cys	missense_variant	Exon 2 of 4	1		ENSP00000392096.1	O95196-3
CSPG5	ENST00000610462.1 link	c.1372C>T	p.Arg458Cys	missense_variant	Exon 3 of 4	5		ENSP00000478923.1	A0A087WUT8

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250546

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461646

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1372C>T (p.R458C) alteration is located in exon 3 (coding exon 3) of the CSPG5 gene. This alteration results from a C to T substitution at nucleotide position 1372, causing the arginine (R) at amino acid position 458 to be replaced by a cysteine (C). 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

Pathogenic

0.57

BayesDel_addAF

Benign

-0.0078

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

.;D;.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.97

.;L;L;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.6

D;D;D;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.83

MutPred

0.83

.;Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);

MVP

0.44

MPC

1.8

ClinPred

0.94

GERP RS

4.4

Varity_R

0.48

gMVP

0.86

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