1-21890111-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001291860.2(HSPG2):c.444G>C(p.Leu148Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,328 control chromosomes in the GnomAD database, including 328,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L148L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.53 ( 23659 hom., cov: 31)

Exomes 𝑓: 0.64 ( 304728 hom. )

Consequence

HSPG2
NM_001291860.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.14

Publications

22 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.164).

BP6

Variant 1-21890111-C-G is Benign according to our data. Variant chr1-21890111-C-G is described in ClinVar as Benign. ClinVar VariationId is 295912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291860.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.444G>C	p.Leu148Leu	synonymous	Exon 6 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.444G>C	p.Leu148Leu	synonymous	Exon 6 of 97	NP_001278789.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.444G>C	p.Leu148Leu	synonymous	Exon 6 of 97	ENSP00000363827.3
HSPG2	ENST00000374673.4	TSL:3	c.198G>C	p.Leu66Leu	synonymous	Exon 3 of 7	ENSP00000497688.1
HSPG2	ENST00000412328.5	TSL:2	n.212G>C		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes

AF:

0.532

AC:

80785

AN:

151840

Hom.:

23657

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.514

Gnomad AMR

AF:

0.484

Gnomad ASJ

AF:

0.757

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.602

Gnomad FIN

AF:

0.643

Gnomad MID

AF:

0.712

Gnomad NFE

AF:

0.664

Gnomad OTH

AF:

0.570

GnomAD2 exomes

AF:

0.577

AC:

145163

AN:

251380

AF XY:

0.594

show subpopulations

Gnomad AFR exome

AF:

0.290

Gnomad AMR exome

AF:

0.416

Gnomad ASJ exome

AF:

0.747

Gnomad EAS exome

AF:

0.373

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.667

Gnomad OTH exome

AF:

0.603

GnomAD4 exome

AF:

0.640

AC:

935043

AN:

1461370

Hom.:

304728

Cov.:

AF XY:

0.641

AC XY:

466196

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.286

AC:

9576

AN:

33472

American (AMR)

AF:

0.425

AC:

19010

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

19611

AN:

26134

East Asian (EAS)

AF:

0.405

AC:

16093

AN:

39698

South Asian (SAS)

AF:

0.594

AC:

51195

AN:

86240

European-Finnish (FIN)

AF:

0.635

AC:

33928

AN:

53402

Middle Eastern (MID)

AF:

0.674

AC:

3874

AN:

5746

European-Non Finnish (NFE)

AF:

0.670

AC:

744243

AN:

1111600

Other (OTH)

AF:

0.621

AC:

37513

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

19219

38438

57656

76875

96094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19044

38088

57132

76176

95220

<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:

0.532

AC:

80798

AN:

151958

Hom.:

23659

Cov.:

AF XY:

0.530

AC XY:

39342

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.294

AC:

12176

AN:

41416

American (AMR)

AF:

0.484

AC:

7387

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.757

AC:

2628

AN:

3470

East Asian (EAS)

AF:

0.369

AC:

1902

AN:

5158

South Asian (SAS)

AF:

0.602

AC:

2901

AN:

4820

European-Finnish (FIN)

AF:

0.643

AC:

6796

AN:

10572

Middle Eastern (MID)

AF:

0.718

AC:

211

AN:

294

European-Non Finnish (NFE)

AF:

0.664

AC:

45124

AN:

67938

Other (OTH)

AF:

0.572

AC:

1204

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1722

3444

5166

6888

8610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<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:

0.622

Hom.:

8317

Bravo

AF:

0.512

Asia WGS

AF:

0.496

AC:

1724

AN:

3478

EpiCase

AF:

0.675

EpiControl

AF:

0.689

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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

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