rs2254358

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The ENST00000374695.8(HSPG2):​c.474G>T​(p.Gly158=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,613,166 control chromosomes in the GnomAD database, including 328,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 23646 hom., cov: 31)
Exomes 𝑓: 0.64 ( 304544 hom. )

Consequence

HSPG2
ENST00000374695.8 synonymous

Scores

1
1

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.592
Variant links:
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 Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.34).
BP6
Variant 1-21890081-C-A is Benign according to our data. Variant chr1-21890081-C-A is described in ClinVar as [Benign]. Clinvar id is 295910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21890081-C-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.592 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HSPG2NM_005529.7 linkuse as main transcriptc.474G>T p.Gly158= synonymous_variant 6/97 ENST00000374695.8 NP_005520.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HSPG2ENST00000374695.8 linkuse as main transcriptc.474G>T p.Gly158= synonymous_variant 6/971 NM_005529.7 ENSP00000363827 P1
HSPG2ENST00000374673.4 linkuse as main transcriptc.231G>T p.Gly77= synonymous_variant 3/73 ENSP00000497688
HSPG2ENST00000412328.5 linkuse as main transcriptn.242G>T non_coding_transcript_exon_variant 3/62
HSPG2ENST00000439717.2 linkuse as main transcriptn.372G>T non_coding_transcript_exon_variant 5/52

Frequencies

GnomAD3 genomes
AF:
0.532
AC:
80751
AN:
151752
Hom.:
23644
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.295
Gnomad AMI
AF:
0.515
Gnomad AMR
AF:
0.484
Gnomad ASJ
AF:
0.758
Gnomad EAS
AF:
0.369
Gnomad SAS
AF:
0.601
Gnomad FIN
AF:
0.644
Gnomad MID
AF:
0.712
Gnomad NFE
AF:
0.664
Gnomad OTH
AF:
0.570
GnomAD3 exomes
AF:
0.577
AC:
145150
AN:
251382
Hom.:
44245
AF XY:
0.594
AC XY:
80668
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.290
Gnomad AMR exome
AF:
0.416
Gnomad ASJ exome
AF:
0.747
Gnomad EAS exome
AF:
0.374
Gnomad SAS exome
AF:
0.597
Gnomad FIN exome
AF:
0.642
Gnomad NFE exome
AF:
0.666
Gnomad OTH exome
AF:
0.603
GnomAD4 exome
AF:
0.640
AC:
934702
AN:
1461298
Hom.:
304544
Cov.:
50
AF XY:
0.641
AC XY:
466034
AN XY:
727006
show subpopulations
Gnomad4 AFR exome
AF:
0.286
Gnomad4 AMR exome
AF:
0.425
Gnomad4 ASJ exome
AF:
0.750
Gnomad4 EAS exome
AF:
0.406
Gnomad4 SAS exome
AF:
0.594
Gnomad4 FIN exome
AF:
0.635
Gnomad4 NFE exome
AF:
0.669
Gnomad4 OTH exome
AF:
0.621
GnomAD4 genome
AF:
0.532
AC:
80763
AN:
151868
Hom.:
23646
Cov.:
31
AF XY:
0.530
AC XY:
39320
AN XY:
74198
show subpopulations
Gnomad4 AFR
AF:
0.294
Gnomad4 AMR
AF:
0.483
Gnomad4 ASJ
AF:
0.758
Gnomad4 EAS
AF:
0.369
Gnomad4 SAS
AF:
0.601
Gnomad4 FIN
AF:
0.644
Gnomad4 NFE
AF:
0.664
Gnomad4 OTH
AF:
0.572
Alfa
AF:
0.645
Hom.:
61575
Bravo
AF:
0.512
Asia WGS
AF:
0.496
AC:
1724
AN:
3478
EpiCase
AF:
0.675
EpiControl
AF:
0.689

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Benign, criteria provided, single submitterclinical testingGeneDxAug 23, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 08, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Lethal Kniest-like syndrome Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Schwartz-Jampel syndrome Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.34
CADD
Benign
1.7
DANN
Uncertain
0.98

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2254358; hg19: chr1-22216574; COSMIC: COSV65930404; COSMIC: COSV65930404; API