rs1869780

chr1-21895962-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005529.7(HSPG2):c.204C>A(p.Asp68Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,614,084 control chromosomes in the GnomAD database, including 16 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D68N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (14 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.314

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=0.004111171).
• BP6: Variant 1-21895962-G-T is Benign according to our data. Variant chr1-21895962-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 283808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21895962-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00144 (219/152308) while in subpopulation EAS AF= 0.00695 (36/5178). AF 95% confidence interval is 0.00516. There are 2 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.204C>A	p.Asp68Glu	missense_variant	3/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.204C>A	p.Asp68Glu	missense_variant	3/97	1	NM_005529.7	P1
HSPG2	ENST00000412328.5	n.141C>A		non_coding_transcript_exon_variant	2/6	2
HSPG2	ENST00000439717.2	n.102C>A		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152190 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00713

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00222 AC: 558 AN: 251192 Hom.: 3 AF XY: 0.00202 AC XY: 274 AN XY: 135764

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00566

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00156 AC: 2281 AN: 1461776 Hom.: 14 Cov.: 32 AF XY: 0.00159 AC XY: 1159 AN XY: 727178

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0150

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152308 Hom.: 2 Cov.: 33 AF XY: 0.00167 AC XY: 124 AN XY: 74474

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00695

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00152

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00191 AC: 232

EpiCase AF: 0.000709

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely 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	GeneDx	Oct 13, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2021	- -

Lethal Kniest-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

HSPG2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Schwartz-Jampel syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.5
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.061
Sift	Benign	0.24	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.0	B
Vest4		0.083
MutPred		0.17		Gain of relative solvent accessibility (P = 0.1259);
MVP		0.49
MPC		0.19
ClinPred		0.018	T
GERP RS		2.8
Varity_R		0.071
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1869780; hg19: chr1-22222455; COSMIC: COSV65975241;