rs761662063
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_005529.7(HSPG2):βc.7210_7233delβ(p.Glu2404_Gly2411del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,612,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000092 ( 0 hom., cov: 33)
Exomes π: 0.00016 ( 0 hom. )
Consequence
HSPG2
NM_005529.7 inframe_deletion
NM_005529.7 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.46
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_005529.7.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSPG2 | NM_005529.7 | c.7210_7233del | p.Glu2404_Gly2411del | inframe_deletion | 56/97 | ENST00000374695.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSPG2 | ENST00000374695.8 | c.7210_7233del | p.Glu2404_Gly2411del | inframe_deletion | 56/97 | 1 | NM_005529.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152164Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000733 AC: 18AN: 245698Hom.: 0 AF XY: 0.0000899 AC XY: 12AN XY: 133444
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GnomAD4 exome AF: 0.000162 AC: 236AN: 1459880Hom.: 0 AF XY: 0.000160 AC XY: 116AN XY: 726142
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GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74336
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 09, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | This variant, c.7210_7233del, results in the deletion of 8 amino acid(s) of the HSPG2 protein (p.Glu2404_Gly2411del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs761662063, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 447559). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 11, 2019 | The HSPG2 c.7210_7233del24; p.Glu2404_Gly2411del variant (rs761662063), to our knowledge, is not described in the medical literature but contains an entry in ClinVar (Variation ID: 447559). It is observed in the non-Finnish European population at an overall frequency of 0.015% (19/126146 alleles) in the Genome Aggregation Database. This variant deletes 8 amino acids (glutamic acid, tyrosine, valine, cysteine, arginine, valine, leucine, glycine), leaving the rest of the protein in frame. Due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at