rs2305562

chr1-21857246-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005529.7(HSPG2):c.5394+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,613,468 control chromosomes in the GnomAD database, including 221,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (19234 hom., cov: 31)
  • Exomes 𝑓: 0.52 (202578 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-21857246-A-G is Benign according to our data. Variant chr1-21857246-A-G is described in ClinVar as [Benign]. Clinvar id is 1220862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.5394+39T>C		intron_variant		ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.5394+39T>C		intron_variant		1	NM_005529.7	P1

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75916 AN: 151812 Hom.: 19217 Cov.: 31

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.519

GnomAD3 exomes AF: 0.504 AC: 126636 AN: 251246 Hom.: 32482 AF XY: 0.503 AC XY: 68253 AN XY: 135804

Gnomad AFR exome AF: 0.420

Gnomad AMR exome AF: 0.484

Gnomad ASJ exome AF: 0.588

Gnomad EAS exome AF: 0.447

Gnomad SAS exome AF: 0.386

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.546

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.524 AC: 766130 AN: 1461538 Hom.: 202578 Cov.: 42 AF XY: 0.522 AC XY: 379589 AN XY: 727066

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.482

Gnomad4 ASJ exome AF: 0.584

Gnomad4 EAS exome AF: 0.487

Gnomad4 SAS exome AF: 0.386

Gnomad4 FIN exome AF: 0.545

Gnomad4 NFE exome AF: 0.538

Gnomad4 OTH exome AF: 0.518

GnomAD4 genome AF: 0.500 AC: 75984 AN: 151930 Hom.: 19234 Cov.: 31 AF XY: 0.499 AC XY: 37017 AN XY: 74224

Gnomad4 AFR AF: 0.428

Gnomad4 AMR AF: 0.480

Gnomad4 ASJ AF: 0.586

Gnomad4 EAS AF: 0.460

Gnomad4 SAS AF: 0.375

Gnomad4 FIN AF: 0.547

Gnomad4 NFE AF: 0.548

Gnomad4 OTH AF: 0.517

Alfa AF: 0.544 Hom.: 29113

Bravo AF: 0.496

Asia WGS AF: 0.435 AC: 1512 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	6.9
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2305562; hg19: chr1-22183739; COSMIC: COSV65970004; COSMIC: COSV65970004;