rs2454290

Variant names:

• chr1-21873328-G-A
• rs2454290
• NM_005529.7:c.3793+47C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-21873328-G-A
• chr1-21873328-G-C
• chr1-21873328-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.3793+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 1,603,690 control chromosomes in the GnomAD database, including 559,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (45166 hom., cov: 32)
  • Exomes 𝑓: 0.84 (514232 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0950
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-21873328-G-A is Benign according to our data. Variant chr1-21873328-G-A is described in ClinVar as Benign. ClinVar VariationId is 1235752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005529.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.3793+47C>T		intron	N/A	NP_005520.4
	HSPG2	NM_001291860.2		c.3796+47C>T		intron	N/A	NP_001278789.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.3793+47C>T		intron	N/A	ENSP00000363827.3
	HSPG2	ENST00000427897.1	TSL:5	n.355+47C>T		intron	N/A	ENSP00000397573.1

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114334 AN: 152024 Hom.: 45165 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.871

Gnomad EAS AF: 0.974

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.763

GnomAD2 exomes AF: 0.831 AC: 208892 AN: 251424 AF XY: 0.829

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.977

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.849

Gnomad OTH exome AF: 0.839

GnomAD4 exome AF: 0.839 AC: 1217163 AN: 1451548 Hom.: 514232 Cov.: 29 AF XY: 0.836 AC XY: 604278 AN XY: 722914

African (AFR) AF: 0.471 AC: 15626 AN: 33210

American (AMR) AF: 0.904 AC: 40439 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 22542 AN: 26088

East Asian (EAS) AF: 0.977 AC: 38747 AN: 39652

South Asian (SAS) AF: 0.729 AC: 62720 AN: 86028

European-Finnish (FIN) AF: 0.856 AC: 45738 AN: 53408

Middle Eastern (MID) AF: 0.784 AC: 4512 AN: 5756

European-Non Finnish (NFE) AF: 0.850 AC: 937155 AN: 1102640

Other (OTH) AF: 0.827 AC: 49684 AN: 60052

GnomAD4 genome AF: 0.752 AC: 114368 AN: 152142 Hom.: 45166 Cov.: 32 AF XY: 0.756 AC XY: 56231 AN XY: 74392

African (AFR) AF: 0.486 AC: 20128 AN: 41452

American (AMR) AF: 0.850 AC: 12998 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 3025 AN: 3472

East Asian (EAS) AF: 0.974 AC: 5048 AN: 5184

South Asian (SAS) AF: 0.734 AC: 3541 AN: 4826

European-Finnish (FIN) AF: 0.866 AC: 9181 AN: 10596

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.852 AC: 57944 AN: 67996

Other (OTH) AF: 0.764 AC: 1616 AN: 2114

Alfa AF: 0.818 Hom.: 151342

Bravo AF: 0.744

Asia WGS AF: 0.836 AC: 2905 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.59
PhyloP100		0.095
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2454290; hg19: chr1-22199821;