chr15-75689744-C-T

Variant names:

• chr15-75689744-C-T
• rs79463888
• NM_001897.5:c.1321G>A

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 22 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: Likely_benign. The variant received -4 ACMG points.

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

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.1321G>A	p.Glu441Lys	missense	Exon 3 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.1321G>A	p.Glu441Lys	missense	Exon 3 of 10	ENSP00000312506.5	Q6UVK1
	CSPG4	ENST00000941445.1		c.253-1653G>A		intron	N/A	ENSP00000611504.1
	CSPG4	ENST00000900311.1		c.252+3326G>A		intron	N/A	ENSP00000570370.1

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 602 AN: 142944 Hom.: 0 Cov.: 34

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

GnomAD2 exomes AF: 0.0455 AC: 8679 AN: 190828 AF XY: 0.0470

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00317 AC: 99 AN: 31254

American (AMR) AF: 0.0122 AC: 456 AN: 37332

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 379 AN: 21498

East Asian (EAS) AF: 0.00503 AC: 183 AN: 36354

South Asian (SAS) AF: 0.0133 AC: 997 AN: 74684

European-Finnish (FIN) AF: 0.0293 AC: 1298 AN: 44344

Middle Eastern (MID) AF: 0.0232 AC: 109 AN: 4692

European-Non Finnish (NFE) AF: 0.0375 AC: 30051 AN: 801190

Other (OTH) AF: 0.0234 AC: 1125 AN: 48060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00152 AC: 62 AN: 40780

American (AMR) AF: 0.00307 AC: 45 AN: 14636

Ashkenazi Jewish (ASJ) AF: 0.00366 AC: 12 AN: 3278

East Asian (EAS) AF: 0.000590 AC: 3 AN: 5082

South Asian (SAS) AF: 0.00532 AC: 24 AN: 4512

European-Finnish (FIN) AF: 0.00989 AC: 93 AN: 9408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00564 AC: 351 AN: 62240

Other (OTH) AF: 0.00557 AC: 11 AN: 1976

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.358 Hom.: 5829

ExAC AF: 0.152 AC: 18434

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.0
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
Mutation Taster		=62/38	polymorphism

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