15-75689744-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001897.5(CSPG4):c.1321G>A(p.Glu441Lys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E441D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (0 hom., cov: 34)
  • Exomes 𝑓: 0.032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSPG4 NM_001897.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97

Genes affected

CSPG4 (HGNC:2466): (chondroitin sulfate proteoglycan 4) A human melanoma-associated chondroitin sulfate proteoglycan plays a role in stabilizing cell-substratum interactions during early events of melanoma cell spreading on endothelial basement membranes. CSPG4 represents an integral membrane chondroitin sulfate proteoglycan expressed by human malignant melanoma cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009054273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSPG4	NM_001897.5	c.1321G>A	p.Glu441Lys	missense_variant	3/10	ENST00000308508.5
CSPG4	XM_047432196.1	c.259G>A	p.Glu87Lys	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSPG4	ENST00000308508.5	c.1321G>A	p.Glu441Lys	missense_variant	3/10	1	NM_001897.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 602 AN: 142944 Hom.: 0 Cov.: 34 FAILED QC

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00116

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00366

Gnomad EAS AF: 0.000589

Gnomad SAS AF: 0.00532

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00564

Gnomad OTH AF: 0.00562

GnomAD3 exomes AF: 0.0455 AC: 8679 AN: 190828 Hom.: 0 AF XY: 0.0470 AC XY: 4837 AN XY: 102822

Gnomad AFR exome AF: 0.00920

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.0198

Gnomad SAS exome AF: 0.0310

Gnomad FIN exome AF: 0.0807

Gnomad NFE exome AF: 0.0617

Gnomad OTH exome AF: 0.0414

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0316 AC: 34697 AN: 1099408 Hom.: 0 Cov.: 93 AF XY: 0.0308 AC XY: 16989 AN XY: 551950

Gnomad4 AFR exome AF: 0.00317

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.00503

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0293

Gnomad4 NFE exome AF: 0.0375

Gnomad4 OTH exome AF: 0.0234

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00421 AC: 602 AN: 143056 Hom.: 0 Cov.: 34 AF XY: 0.00448 AC XY: 313 AN XY: 69934

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00366

Gnomad4 EAS AF: 0.000590

Gnomad4 SAS AF: 0.00532

Gnomad4 FIN AF: 0.00989

Gnomad4 NFE AF: 0.00564

Gnomad4 OTH AF: 0.00557

Alfa AF: 0.0807 Hom.: 407

ExAC AF: 0.152 AC: 18434

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.28
MPC		0.97
ClinPred		0.039	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.96

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: rs79463888; hg19: chr15-75982085; COSMIC: COSV57890918;