3-47569090-T-C

Position:

• chr3-47569090-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001206943.2(CSPG5):​c.1520A>G​(p.Tyr507Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CSPG5 NM_001206943.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31124657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSPG5	NM_006574.4	c.1458+62A>G		intron_variant		ENST00000264723.9	NP_006565.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSPG5	ENST00000383738.6	c.1520A>G	p.Tyr507Cys	missense_variant	4/5	1		ENSP00000373244.2
CSPG5	ENST00000264723.9	c.1458+62A>G		intron_variant		1	NM_006574.4	ENSP00000264723.4
CSPG5	ENST00000456150.5	c.1044+62A>G		intron_variant		1		ENSP00000392096.1
CSPG5	ENST00000610462.1	c.1382+3596A>G		intron_variant		5		ENSP00000478923.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398204 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691476

Gnomad4 AFR exome AF: 0.0000327

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.1520A>G (p.Y507C) alteration is located in exon 4 (coding exon 4) of the CSPG5 gene. This alteration results from a A to G substitution at nucleotide position 1520, causing the tyrosine (Y) at amino acid position 507 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	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.11
Sift	Benign	0.056	T
Sift4G	Benign	0.070	T
Polyphen		0.0090	B
Vest4		0.32
MutPred		0.73		Gain of disorder (P = 0.0172);
MVP		0.24
MPC		0.70
ClinPred		0.45	T
GERP RS		1.5
Varity_R		0.14
gMVP		0.23

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

Other links and lift over

dbSNP: rs2031421892; hg19: chr3-47610580;