1-21823667-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.12952C>A(p.Arg4318Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.18 in 1,613,166 control chromosomes in the GnomAD database, including 28,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1837 hom., cov: 33)

Exomes 𝑓: 0.18 ( 26298 hom. )

Consequence

HSPG2
NM_005529.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.73

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 links:

LDLRAD2 (HGNC:32071): (low density lipoprotein receptor class A domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LDLRAD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 1-21823667-G-T is Benign according to our data. Variant chr1-21823667-G-T is described in CliVar as Benign. Clinvar id is 295701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21823667-G-T is described in CliVar as Benign. Clinvar id is 295701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21823667-G-T is described in CliVar as Benign. Clinvar id is 295701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21823667-G-T is described in CliVar as Benign. Clinvar id is 295701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.12952C>A	p.Arg4318Arg	synonymous_variant	Exon 96 of 97	ENST00000374695.8	NP_005520.4	P98160
LDLRAD2	NM_001013693.3 link	c.*1452G>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000344642.7	NP_001013715.2	Q5SZI1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.12952C>A	p.Arg4318Arg	synonymous_variant	Exon 96 of 97	1	NM_005529.7	ENSP00000363827.3		P98160
LDLRAD2	ENST00000344642.7 link	c.*1452G>T		3_prime_UTR_variant	Exon 5 of 5	2	NM_001013693.3	ENSP00000340988.2		Q5SZI1

Frequencies

GnomAD3 genomes

AF:

0.140

AC:

21312

AN:

152066

Hom.:

1837

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0372

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.176

Gnomad OTH

AF:

0.136

GnomAD2 exomes

AF:

0.178

AC:

44662

AN:

250734

AF XY:

0.187

show subpopulations

Gnomad AFR exome

AF:

0.0345

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.160

Gnomad FIN exome

AF:

0.235

Gnomad NFE exome

AF:

0.179

Gnomad OTH exome

AF:

0.169

GnomAD4 exome

AF:

0.184

AC:

269025

AN:

1460982

Hom.:

26298

Cov.:

AF XY:

0.187

AC XY:

136092

AN XY:

726844

show subpopulations

African (AFR)

AF:

0.0319

AC:

1067

AN:

33480

American (AMR)

AF:

0.127

AC:

5680

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.174

AC:

4535

AN:

26134

East Asian (EAS)

AF:

0.172

AC:

6818

AN:

39700

South Asian (SAS)

AF:

0.282

AC:

24321

AN:

86246

European-Finnish (FIN)

AF:

0.235

AC:

12458

AN:

52988

Middle Eastern (MID)

AF:

0.132

AC:

763

AN:

5768

European-Non Finnish (NFE)

AF:

0.182

AC:

202495

AN:

1111568

Other (OTH)

AF:

0.180

AC:

10888

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

12311

24622

36932

49243

61554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7248

14496

21744

28992

36240

<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:

0.140

AC:

21310

AN:

152184

Hom.:

1837

Cov.:

AF XY:

0.144

AC XY:

10700

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0371

AC:

1541

AN:

41542

American (AMR)

AF:

0.128

AC:

1953

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

609

AN:

3472

East Asian (EAS)

AF:

0.167

AC:

864

AN:

5164

South Asian (SAS)

AF:

0.295

AC:

1426

AN:

4828

European-Finnish (FIN)

AF:

0.241

AC:

2557

AN:

10594

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.176

AC:

11961

AN:

67964

Other (OTH)

AF:

0.138

AC:

291

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

921

1842

2762

3683

4604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<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:

0.125

Hom.:

658

Bravo

AF:

0.126

Asia WGS

AF:

0.238

AC:

828

AN:

3478

EpiCase

AF:

0.164

EpiControl

AF:

0.177

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Aug 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal Kniest-like syndrome

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

3.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Mutation Taster

=87/13

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over