1-21855402-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.5899G>A(p.Val1967Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0563 in 1,612,996 control chromosomes in the GnomAD database, including 3,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 179 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2879 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.93

Publications

18 publications found

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]

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

HSPG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018017888).

BP6

Variant 1-21855402-C-T is Benign according to our data. Variant chr1-21855402-C-T is described in ClinVar as Benign. ClinVar VariationId is 295823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.5899G>A	p.Val1967Ile	missense_variant	Exon 47 of 97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.5899G>A	p.Val1967Ile	missense_variant	Exon 47 of 97	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.0404

AC:

6150

AN:

152174

Hom.:

178

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00951

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.0342

Gnomad ASJ

AF:

0.0397

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0428

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0584

Gnomad OTH

AF:

0.0454

GnomAD2 exomes

AF:

0.0487

AC:

12086

AN:

248110

AF XY:

0.0536

show subpopulations

Gnomad AFR exome

AF:

0.00821

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0419

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.0438

Gnomad NFE exome

AF:

0.0562

Gnomad OTH exome

AF:

0.0515

GnomAD4 exome

AF:

0.0580

AC:

84661

AN:

1460704

Hom.:

2879

Cov.:

AF XY:

0.0599

AC XY:

43548

AN XY:

726616

show subpopulations

African (AFR)

AF:

0.00783

AC:

262

AN:

33478

American (AMR)

AF:

0.0248

AC:

1105

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.0423

AC:

1105

AN:

26104

East Asian (EAS)

AF:

0.000227

AC:

AN:

39696

South Asian (SAS)

AF:

0.109

AC:

9389

AN:

86038

European-Finnish (FIN)

AF:

0.0449

AC:

2374

AN:

52900

Middle Eastern (MID)

AF:

0.0688

AC:

395

AN:

5740

European-Non Finnish (NFE)

AF:

0.0601

AC:

66779

AN:

1111738

Other (OTH)

AF:

0.0537

AC:

3243

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

5730

11460

17190

22920

28650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2474

4948

7422

9896

12370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0404

AC:

6153

AN:

152292

Hom.:

179

Cov.:

AF XY:

0.0399

AC XY:

2972

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00948

AC:

394

AN:

41564

American (AMR)

AF:

0.0341

AC:

522

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0397

AC:

138

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.105

AC:

506

AN:

4822

European-Finnish (FIN)

AF:

0.0428

AC:

455

AN:

10626

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0584

AC:

3972

AN:

68014

Other (OTH)

AF:

0.0449

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

308

616

925

1233

1541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0515

Hom.:

447

Bravo

AF:

0.0363

TwinsUK

AF:

0.0647

AC:

240

ALSPAC

AF:

0.0625

AC:

241

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.0565

AC:

486

ExAC

AF:

0.0498

AC:

6042

Asia WGS

AF:

0.0350

AC:

122

AN:

3478

EpiCase

AF:

0.0565

EpiControl

AF:

0.0541

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal Kniest-like syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Schwartz-Jampel syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Jun 03, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.5

PhyloP100

1.9

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.58

REVEL

Benign

0.24

Sift

Benign

0.19

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.27

MPC

0.59

ClinPred

0.0077

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.13

gMVP

0.31

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over