rs2290501

chr1-21847933-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):c.7873+25A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,542 control chromosomes in the GnomAD database, including 93,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11185 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82755 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.665

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-21847933-T-G is Benign according to our data. Variant chr1-21847933-T-G is described in ClinVar as [Benign]. Clinvar id is 1256801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21847933-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.7873+25A>C		intron_variant		ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.7873+25A>C		intron_variant		1	NM_005529.7	P1
HSPG2	ENST00000453796.1	n.26A>C		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56142 AN: 151926 Hom.: 11153 Cov.: 32

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.367

GnomAD3 exomes AF: 0.325 AC: 81523 AN: 250788 Hom.: 14439 AF XY: 0.333 AC XY: 45190 AN XY: 135618

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.350

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.475

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.331 AC: 483107 AN: 1461498 Hom.: 82755 Cov.: 52 AF XY: 0.334 AC XY: 243072 AN XY: 727060

Gnomad4 AFR exome AF: 0.541

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.334

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.370 AC: 56229 AN: 152044 Hom.: 11185 Cov.: 32 AF XY: 0.366 AC XY: 27204 AN XY: 74322

Gnomad4 AFR AF: 0.526

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.482

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.368

Alfa AF: 0.327 Hom.: 13607

Bravo AF: 0.366

Asia WGS AF: 0.350 AC: 1217 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.309

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal Kniest-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Schwartz-Jampel syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.0
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2290501; hg19: chr1-22174426; COSMIC: COSV65971017; COSMIC: COSV65971017;