rs2305562

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.5394+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,613,468 control chromosomes in the GnomAD database, including 221,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19234 hom., cov: 31)

Exomes 𝑓: 0.52 ( 202578 hom. )

Consequence

HSPG2
NM_005529.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.67

Publications

12 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 (BayesDel_noAF=-0.77).

BP6

Variant 1-21857246-A-G is Benign according to our data. Variant chr1-21857246-A-G is described in ClinVar as Benign. ClinVar VariationId is 1220862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.5394+39T>C		intron_variant	Intron 43 of 96	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.5394+39T>C		intron_variant	Intron 43 of 96	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.500

AC:

75916

AN:

151812

Hom.:

19217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.428

Gnomad AMI

AF:

0.477

Gnomad AMR

AF:

0.480

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.459

Gnomad SAS

AF:

0.374

Gnomad FIN

AF:

0.547

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.548

Gnomad OTH

AF:

0.519

GnomAD2 exomes

AF:

0.504

AC:

126636

AN:

251246

AF XY:

0.503

show subpopulations

Gnomad AFR exome

AF:

0.420

Gnomad AMR exome

AF:

0.484

Gnomad ASJ exome

AF:

0.588

Gnomad EAS exome

AF:

0.447

Gnomad FIN exome

AF:

0.551

Gnomad NFE exome

AF:

0.546

Gnomad OTH exome

AF:

0.519

GnomAD4 exome

AF:

0.524

AC:

766130

AN:

1461538

Hom.:

202578

Cov.:

AF XY:

0.522

AC XY:

379589

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.425

AC:

14222

AN:

33476

American (AMR)

AF:

0.482

AC:

21573

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

15262

AN:

26134

East Asian (EAS)

AF:

0.487

AC:

19335

AN:

39698

South Asian (SAS)

AF:

0.386

AC:

33304

AN:

86244

European-Finnish (FIN)

AF:

0.545

AC:

29083

AN:

53366

Middle Eastern (MID)

AF:

0.588

AC:

3391

AN:

5768

European-Non Finnish (NFE)

AF:

0.538

AC:

598667

AN:

1111740

Other (OTH)

AF:

0.518

AC:

31293

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

24588

49176

73764

98352

122940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16752

33504

50256

67008

83760

<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:

0.500

AC:

75984

AN:

151930

Hom.:

19234

Cov.:

AF XY:

0.499

AC XY:

37017

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.428

AC:

17726

AN:

41410

American (AMR)

AF:

0.480

AC:

7329

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

2035

AN:

3470

East Asian (EAS)

AF:

0.460

AC:

2369

AN:

5152

South Asian (SAS)

AF:

0.375

AC:

1806

AN:

4816

European-Finnish (FIN)

AF:

0.547

AC:

5782

AN:

10580

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.548

AC:

37230

AN:

67918

Other (OTH)

AF:

0.517

AC:

1092

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1987

3974

5961

7948

9935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

678

1356

2034

2712

3390

<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:

0.542

Hom.:

33863

Bravo

AF:

0.496

Asia WGS

AF:

0.435

AC:

1512

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 09, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.9

(source)

DANN

Benign

0.74

PhyloP100

1.7

Mutation Taster

=100/0

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