rs2229489

chr1-21842352-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.37

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HSPG2
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.8939T>A	p.Leu2980His	missense_variant	68/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.8939T>A	p.Leu2980His	missense_variant	68/97	1	NM_005529.7	P1

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6167 AN: 152102 Hom.: 177 Cov.: 33

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

GnomAD3 exomes AF: 0.0490 AC: 12066 AN: 246234 Hom.: 423 AF XY: 0.0539 AC XY: 7208 AN XY: 133672

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 SAS exome AF: 0.105

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.: 34 AF XY: 0.0601 AC XY: 43549 AN XY: 724330

Gnomad4 AFR exome AF: 0.00811

Gnomad4 AMR exome AF: 0.0249

Gnomad4 ASJ exome AF: 0.0426

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.0450

Gnomad4 NFE exome AF: 0.0603

Gnomad4 OTH exome AF: 0.0540

GnomAD4 genome AF: 0.0406 AC: 6175 AN: 152220 Hom.: 179 Cov.: 33 AF XY: 0.0401 AC XY: 2983 AN XY: 74426

Gnomad4 AFR AF: 0.00961

Gnomad4 AMR AF: 0.0342

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0432

Gnomad4 NFE AF: 0.0586

Gnomad4 OTH AF: 0.0454

Alfa AF: 0.0540 Hom.: 198

Bravo AF: 0.0365

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0623 AC: 240

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0557 AC: 479

ExAC AF: 0.0496 AC: 6024

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Lethal Kniest-like syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	15
Dann	Benign	0.26
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.024	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.070
Sift	Benign	1.0	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.26
ClinPred		0.00051	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs2229489; hg19: chr1-22168845;