rs8023621

Variant names:

• chr15-75677729-C-T
• rs8023621
• NM_001897.5:c.5108G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001897.5(CSPG4):​c.5108G>A​(p.Arg1703His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,604,012 control chromosomes in the GnomAD database, including 119,864 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8900 hom., cov: 32)
  • Exomes 𝑓: 0.38 (110964 hom.)
• Consequence: CSPG4 NM_001897.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• Publications: 27 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016655624).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

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.5108G>A	p.Arg1703His	missense	Exon 9 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.5108G>A	p.Arg1703His	missense	Exon 9 of 10	ENSP00000312506.5	Q6UVK1
	CSPG4	ENST00000941445.1		c.2387G>A	p.Arg796His	missense	Exon 9 of 10	ENSP00000611504.1
	CSPG4	ENST00000900311.1		c.1571G>A	p.Arg524His	missense	Exon 8 of 9	ENSP00000570370.1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50073 AN: 151942 Hom.: 8893 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.346 AC: 83510 AN: 241124 AF XY: 0.347

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.385 AC: 558819 AN: 1451952 Hom.: 110964 Cov.: 45 AF XY: 0.382 AC XY: 275882 AN XY: 722386

African (AFR) AF: 0.191 AC: 6237 AN: 32684

American (AMR) AF: 0.311 AC: 13334 AN: 42890

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 10733 AN: 25776

East Asian (EAS) AF: 0.165 AC: 6410 AN: 38798

South Asian (SAS) AF: 0.270 AC: 23021 AN: 85366

European-Finnish (FIN) AF: 0.392 AC: 20785 AN: 52956

Middle Eastern (MID) AF: 0.291 AC: 1669 AN: 5732

European-Non Finnish (NFE) AF: 0.411 AC: 455026 AN: 1107794

Other (OTH) AF: 0.360 AC: 21604 AN: 59956

GnomAD4 genome AF: 0.329 AC: 50085 AN: 152060 Hom.: 8900 Cov.: 32 AF XY: 0.326 AC XY: 24235 AN XY: 74366

African (AFR) AF: 0.205 AC: 8489 AN: 41484

American (AMR) AF: 0.370 AC: 5653 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1442 AN: 3470

East Asian (EAS) AF: 0.181 AC: 935 AN: 5174

South Asian (SAS) AF: 0.255 AC: 1232 AN: 4822

European-Finnish (FIN) AF: 0.385 AC: 4067 AN: 10574

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27158 AN: 67942

Other (OTH) AF: 0.326 AC: 687 AN: 2110

Alfa AF: 0.376 Hom.: 30753

Bravo AF: 0.320

TwinsUK AF: 0.409 AC: 1518

ALSPAC AF: 0.411 AC: 1583

ESP6500AA AF: 0.202 AC: 887

ESP6500EA AF: 0.400 AC: 3435

ExAC AF: 0.346 AC: 42068

Asia WGS AF: 0.225 AC: 785 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.025
Sift	Benign	0.061	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.10
MPC		0.41
ClinPred		0.016	T
GERP RS		3.1
Varity_R		0.075
gMVP		0.56
Mutation Taster		=97/3	polymorphism (auto)

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: rs8023621; hg19: chr15-75970070; COSMIC: COSV57892403; COSMIC: COSV57892403;