rs2124368

Variant names:

• chr1-21858986-C-T
• rs2124368
• NM_005529.7:c.5293+580G>A

Variant summary

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

The NM_005529.7(HSPG2):​c.5293+580G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 151,786 control chromosomes in the GnomAD database, including 1,374 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 0.13 (1374 hom., cov: 32)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.5293+580G>A		intron_variant	Intron 42 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.5293+580G>A		intron_variant	Intron 42 of 96	1	NM_005529.7	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19071 AN: 151668 Hom.: 1373 Cov.: 32

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.129

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

GnomAD4 genome AF: 0.126 AC: 19075 AN: 151786 Hom.: 1374 Cov.: 32 AF XY: 0.126 AC XY: 9372 AN XY: 74180

African (AFR) AF: 0.0395 AC: 1636 AN: 41398

American (AMR) AF: 0.128 AC: 1957 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3470

East Asian (EAS) AF: 0.124 AC: 640 AN: 5156

South Asian (SAS) AF: 0.250 AC: 1198 AN: 4800

European-Finnish (FIN) AF: 0.165 AC: 1732 AN: 10522

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11069 AN: 67894

Other (OTH) AF: 0.133 AC: 279 AN: 2102

Alfa AF: 0.137 Hom.: 1323

Bravo AF: 0.119

Asia WGS AF: 0.204 AC: 710 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.061
DANN	Benign	0.60
PhyloP100		-1.5
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: rs2124368; hg19: chr1-22185479;