rs2229489

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.8939T>A(p.Leu2980His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,609,560 control chromosomes in the GnomAD database, including 3,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 179 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2886 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.37

Publications

13 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
Silverman-Handmaker type dyssegmental dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen
Schwartz-Jampel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HSPG2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005529.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.004461229).

BP6

Variant 1-21842352-A-T is Benign according to our data. Variant chr1-21842352-A-T is described in ClinVar as Benign. ClinVar VariationId is 295765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0967 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.8939T>A	p.Leu2980His	missense	Exon 68 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.8942T>A	p.Leu2981His	missense	Exon 68 of 97	NP_001278789.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.8939T>A	p.Leu2980His	missense	Exon 68 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes

AF:

0.0405

AC:

6167

AN:

152102

Hom.:

177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00951

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.0343

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0586

Gnomad OTH

AF:

0.0458

GnomAD2 exomes

AF:

0.0490

AC:

12066

AN:

246234

AF XY:

0.0539

show subpopulations

Gnomad AFR exome

AF:

0.00839

Gnomad AMR exome

AF:

0.0237

Gnomad ASJ exome

AF:

0.0421

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.0441

Gnomad NFE exome

AF:

0.0568

Gnomad OTH exome

AF:

0.0514

GnomAD4 exome

AF:

0.0581

AC:

84728

AN:

1457340

Hom.:

2886

Cov.:

AF XY:

0.0601

AC XY:

43549

AN XY:

724330

show subpopulations

African (AFR)

AF:

0.00811

AC:

271

AN:

33422

American (AMR)

AF:

0.0249

AC:

1106

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.0426

AC:

1110

AN:

26050

East Asian (EAS)

AF:

0.000202

AC:

AN:

39588

South Asian (SAS)

AF:

0.109

AC:

9331

AN:

85938

European-Finnish (FIN)

AF:

0.0450

AC:

2357

AN:

52376

Middle Eastern (MID)

AF:

0.0701

AC:

403

AN:

5750

European-Non Finnish (NFE)

AF:

0.0603

AC:

66890

AN:

1109548

Other (OTH)

AF:

0.0540

AC:

3252

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

4543

9086

13630

18173

22716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2480

4960

7440

9920

12400

<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:

0.0406

AC:

6175

AN:

152220

Hom.:

179

Cov.:

AF XY:

0.0401

AC XY:

2983

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00961

AC:

399

AN:

41534

American (AMR)

AF:

0.0342

AC:

523

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

139

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.104

AC:

503

AN:

4824

European-Finnish (FIN)

AF:

0.0432

AC:

458

AN:

10604

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0586

AC:

3986

AN:

68010

Other (OTH)

AF:

0.0454

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

330

660

989

1319

1649

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:

0.0540

Hom.:

198

Bravo

AF:

0.0365

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Lethal Kniest-like syndrome (2)

Schwartz-Jampel syndrome (2)

Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.066

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.024

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

PhyloP100

3.4

PrimateAI

Benign

0.35

PROVEAN

Benign

2.3

REVEL

Benign

0.070

Sift

Benign

1.0

Sift4G

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over