1-21842308-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.8983A>G(p.Ser2995Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 1,613,086 control chromosomes in the GnomAD database, including 6,654 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2995S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 970 hom., cov: 33)

Exomes 𝑓: 0.083 ( 5684 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.183

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a glycosylation_site O-linked (Xyl...) (chondroitin sulfate) serine (size 0) in uniprot entity PGBM_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0016708672).

BP6

Variant 1-21842308-T-C is Benign according to our data. Variant chr1-21842308-T-C is described in ClinVar as [Benign]. Clinvar id is 295764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.8983A>G	p.Ser2995Gly	missense_variant	Exon 68 of 97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.8983A>G	p.Ser2995Gly	missense_variant	Exon 68 of 97	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15600

AN:

152158

Hom.:

968

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.0681

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.0557

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0804

Gnomad OTH

AF:

0.107

GnomAD3 exomes

AF:

0.0760

AC:

19020

AN:

250160

Hom.:

947

AF XY:

0.0778

AC XY:

10527

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.0411

Gnomad ASJ exome

AF:

0.0564

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0591

Gnomad NFE exome

AF:

0.0794

Gnomad OTH exome

AF:

0.0799

GnomAD4 exome

AF:

0.0828

AC:

120980

AN:

1460810

Hom.:

5684

Cov.:

AF XY:

0.0837

AC XY:

60846

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.192

Gnomad4 AMR exome

AF:

0.0441

Gnomad4 ASJ exome

AF:

0.0564

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.115

Gnomad4 FIN exome

AF:

0.0595

Gnomad4 NFE exome

AF:

0.0832

Gnomad4 OTH exome

AF:

0.0827

GnomAD4 genome

AF:

0.103

AC:

15622

AN:

152276

Hom.:

970

Cov.:

AF XY:

0.0982

AC XY:

7315

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.178

Gnomad4 AMR

AF:

0.0681

Gnomad4 ASJ

AF:

0.0533

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.109

Gnomad4 FIN

AF:

0.0557

Gnomad4 NFE

AF:

0.0804

Gnomad4 OTH

AF:

0.106

Alfa

AF:

0.0807

Hom.:

1095

Bravo

AF:

0.105

TwinsUK

AF:

0.0930

AC:

345

ALSPAC

AF:

0.0898

AC:

346

ESP6500AA

AF:

0.181

AC:

799

ESP6500EA

AF:

0.0767

AC:

660

ExAC

AF:

0.0798

AC:

9687

Asia WGS

AF:

0.0540

AC:

186

AN:

3478

EpiCase

AF:

0.0776

EpiControl

AF:

0.0755

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2018

GeneDx

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

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.1

DANN

Benign

0.27

DEOGEN2

Benign

0.064

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.93

PrimateAI

Benign

0.35

PROVEAN

Benign

1.3

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.046

MPC

0.18

ClinPred

0.00020

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over