chr15-75690151-G-A

Variant names:

• chr15-75690151-G-A
• rs76827801
• NM_001897.5:c.914C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001897.5(CSPG4):​c.914C>T​(p.Thr305Met) variant causes a missense change. The variant allele was found at a frequency of 0.00903 in 142,802 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSPG4 NM_001897.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.15
• Publications: 7 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=0.003302157).
• BP6: Variant 15-75690151-G-A is Benign according to our data. Variant chr15-75690151-G-A is described in ClinVar as Benign. ClinVar VariationId is 402567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.914C>T	p.Thr305Met	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.914C>T	p.Thr305Met	missense	Exon 3 of 10	ENSP00000312506.5	Q6UVK1
	CSPG4	ENST00000941445.1		c.253-2060C>T		intron	N/A	ENSP00000611504.1
	CSPG4	ENST00000900311.1		c.252+2919C>T		intron	N/A	ENSP00000570370.1

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1284 AN: 142732 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00293

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000663

Gnomad MID AF: 0.00685

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00914

GnomAD2 exomes AF: 0.00786 AC: 1926 AN: 244940 AF XY: 0.00666

Gnomad AFR exome AF: 0.0727

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.00394

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00526

Gnomad OTH exome AF: 0.00502

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00477 AC: 6847 AN: 1435236 Hom.: 0 Cov.: 34 AF XY: 0.00465 AC XY: 3320 AN XY: 714496

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

African (AFR) AF: 0.0634 AC: 1722 AN: 27180

American (AMR) AF: 0.00382 AC: 167 AN: 43700

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 61 AN: 25686

East Asian (EAS) AF: 0.000462 AC: 18 AN: 38948

South Asian (SAS) AF: 0.00116 AC: 99 AN: 85570

European-Finnish (FIN) AF: 0.00145 AC: 76 AN: 52256

Middle Eastern (MID) AF: 0.0125 AC: 69 AN: 5524

European-Non Finnish (NFE) AF: 0.00393 AC: 4313 AN: 1097686

Other (OTH) AF: 0.00549 AC: 322 AN: 58686

⚠️ 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 AF: 0.00903 AC: 1290 AN: 142802 Hom.: 0 Cov.: 33 AF XY: 0.00911 AC XY: 637 AN XY: 69902

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

African (AFR) AF: 0.0313 AC: 1065 AN: 34032

American (AMR) AF: 0.00398 AC: 59 AN: 14810

Ashkenazi Jewish (ASJ) AF: 0.00293 AC: 10 AN: 3418

East Asian (EAS) AF: 0.000777 AC: 4 AN: 5148

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4788

European-Finnish (FIN) AF: 0.000663 AC: 7 AN: 10560

Middle Eastern (MID) AF: 0.00741 AC: 2 AN: 270

European-Non Finnish (NFE) AF: 0.00179 AC: 120 AN: 66874

Other (OTH) AF: 0.00904 AC: 18 AN: 1992

⚠️ 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: 0.0138 Hom.: 0

ExAC AF: 0.0206 AC: 2502

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0033	T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.031	D
Polyphen		0.99	D
Vest4		0.24
MPC		0.91
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.079
gMVP		0.62
Mutation Taster		=74/26	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: rs76827801; hg19: chr15-75982492; COSMIC: COSV57889988;