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

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 -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 ClinVar as Benign. ClinVar VariationId 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPG2	NM_005529.7	MANE Select	c.12952C>A	p.Arg4318Arg	synonymous	Exon 96 of 97	NP_005520.4
LDLRAD2	NM_001013693.3	MANE Select	c.*1452G>T		3_prime_UTR	Exon 5 of 5	NP_001013715.2	Q5SZI1
HSPG2	NM_001291860.2		c.12955C>A	p.Arg4319Arg	synonymous	Exon 96 of 97	NP_001278789.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.12952C>A	p.Arg4318Arg	synonymous	Exon 96 of 97	ENSP00000363827.3	P98160
LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*1452G>T		3_prime_UTR	Exon 5 of 5	ENSP00000340988.2	Q5SZI1
LDLRAD2	ENST00000543870.1	TSL:1	c.*219-243G>T		intron	N/A	ENSP00000444097.1	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

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)

Computational scores

Source: dbNSFP v4.9

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

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