15-75675561-A-T

Variant names:

• chr15-75675561-A-T
• rs1893876886
• NM_001897.5:c.6958T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001897.5(CSPG4):​c.6958T>A​(p.Tyr2320Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y2320H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CSPG4 NM_001897.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.19
• Publications: 0 publications found

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]

CSPG4 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001897.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPG4	NM_001897.5	MANE Select	c.6958T>A	p.Tyr2320Asn	missense	Exon 10 of 10	NP_001888.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPG4	ENST00000308508.5	TSL:1 MANE Select	c.6958T>A	p.Tyr2320Asn	missense	Exon 10 of 10	ENSP00000312506.5	Q6UVK1
	CSPG4	ENST00000941445.1		c.4237T>A	p.Tyr1413Asn	missense	Exon 10 of 10	ENSP00000611504.1
	CSPG4	ENST00000900311.1		c.3421T>A	p.Tyr1141Asn	missense	Exon 9 of 9	ENSP00000570370.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354860 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 662304

African (AFR) AF: 0.00 AC: 0 AN: 29970

American (AMR) AF: 0.00 AC: 0 AN: 28388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19632

East Asian (EAS) AF: 0.00 AC: 0 AN: 38436

South Asian (SAS) AF: 0.00 AC: 0 AN: 68974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4922

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1059970

Other (OTH) AF: 0.00 AC: 0 AN: 55584

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.44		Gain of disorder (P = 0.0227)
MVP		0.57
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.87
gMVP		0.79

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

Other links and lift over

dbSNP: rs1893876886; hg19: chr15-75967902;