3-47572863-T-G

Variant names:

• chr3-47572863-T-G
• rs2031577131
• NM_006574.4:c.1205A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006574.4(CSPG5):​c.1205A>C​(p.Gln402Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,064 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CSPG5 NM_006574.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSPG5	NM_006574.4	c.1205A>C	p.Gln402Pro	missense_variant	Exon 3 of 5	ENST00000264723.9	NP_006565.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSPG5	ENST00000264723.9	c.1205A>C	p.Gln402Pro	missense_variant	Exon 3 of 5	1	NM_006574.4	ENSP00000264723.4
CSPG5	ENST00000383738.6	c.1205A>C	p.Gln402Pro	missense_variant	Exon 3 of 5	1		ENSP00000373244.2
CSPG5	ENST00000456150.5	c.791A>C	p.Gln264Pro	missense_variant	Exon 2 of 4	1		ENSP00000392096.1
CSPG5	ENST00000610462.1	c.1205A>C	p.Gln402Pro	missense_variant	Exon 3 of 4	5		ENSP00000478923.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456064 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723568

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1205A>C (p.Q402P) alteration is located in exon 3 (coding exon 3) of the CSPG5 gene. This alteration results from a A to C substitution at nucleotide position 1205, causing the glutamine (Q) at amino acid position 402 to be replaced by a proline (P). 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	0.94
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N;N;N;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.024	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.90
MutPred		0.38		.;Loss of catalytic residue at Q402 (P = 0.0528);Loss of catalytic residue at Q402 (P = 0.0528);Loss of catalytic residue at Q402 (P = 0.0528);
MVP		0.52
MPC		1.7
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.37
gMVP		0.99

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: rs2031577131; hg19: chr3-47614353;