1-21912282-C-G

Variant names:

• chr1-21912282-C-G
• rs1002480
• NM_005529.7:c.64-15972G>C

Variant summary

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

The NM_005529.7(HSPG2):​c.64-15972G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,858 control chromosomes in the GnomAD database, including 13,202 homozygotes. 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: 𝑓 0.40 (13202 hom., cov: 31)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 6 publications found

Genes affected

HSPG2 (HGNC:5273): (heparan sulfate proteoglycan 2) This gene encodes the perlecan protein, which consists of a core protein to which three long chains of glycosaminoglycans (heparan sulfate or chondroitin sulfate) are attached. The perlecan protein is a large multidomain proteoglycan that binds to and cross-links many extracellular matrix components and cell-surface molecules. It has been shown that this protein interacts with laminin, prolargin, collagen type IV, FGFBP1, FBLN2, FGF7 and transthyretin, etc., and it plays essential roles in multiple biological activities. Perlecan is a key component of the vascular extracellular matrix, where it helps to maintain the endothelial barrier function. It is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. It can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation. It is a major component of basement membranes, where it is involved in the stabilization of other molecules as well as being involved with glomerular permeability to macromolecules and cell adhesion. Mutations in this gene cause Schwartz-Jampel syndrome type 1, Silverman-Handmaker type of dyssegmental dysplasia, and tardive dyskinesia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

HSPG2 Gene-Disease associations (from GenCC):

• Schwartz-Jampel syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Schwartz-Jampel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.64-15972G>C		intron_variant	Intron 1 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.64-15972G>C		intron_variant	Intron 1 of 96	1	NM_005529.7	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61276 AN: 151738 Hom.: 13183 Cov.: 31

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.388

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.404 AC: 61335 AN: 151858 Hom.: 13202 Cov.: 31 AF XY: 0.409 AC XY: 30346 AN XY: 74210

African (AFR) AF: 0.488 AC: 20180 AN: 41386

American (AMR) AF: 0.492 AC: 7506 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 900 AN: 3466

East Asian (EAS) AF: 0.717 AC: 3700 AN: 5160

South Asian (SAS) AF: 0.427 AC: 2055 AN: 4810

European-Finnish (FIN) AF: 0.352 AC: 3711 AN: 10536

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21939 AN: 67946

Other (OTH) AF: 0.387 AC: 814 AN: 2106

Alfa AF: 0.342 Hom.: 1219

Bravo AF: 0.417

Asia WGS AF: 0.531 AC: 1850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.0
DANN	Benign	0.52
PhyloP100		0.31
Mutation Taster		=100/0	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: rs1002480; hg19: chr1-22238775;