chr15-75675857-T-G

Position:

• chr15-75675857-T-G

Variant summary

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

The NM_001897.5(CSPG4):​c.6662A>C​(p.Asn2221Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSPG4 NM_001897.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76

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 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=0.31283858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSPG4	NM_001897.5	c.6662A>C	p.Asn2221Thr	missense_variant	10/10	ENST00000308508.5	NP_001888.2
CSPG4	XM_047432196.1	c.5600A>C	p.Asn1867Thr	missense_variant	10/10		XP_047288152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSPG4	ENST00000308508.5	c.6662A>C	p.Asn2221Thr	missense_variant	10/10	1	NM_001897.5	ENSP00000312506.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Sep 03, 2024

The c.6662A>C (p.N2221T) alteration is located in exon 10 (coding exon 10) of the CSPG4 gene. This alteration results from a A to C substitution at nucleotide position 6662, causing the asparagine (N) at amino acid position 2221 to be replaced by a threonine (T). 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	0.25
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.79	P
Vest4		0.48
MutPred		0.46		Loss of stability (P = 0.0434);
MVP		0.30
MPC		0.53
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-75968198;