rs140476180

chr1-21851608-C-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.7096G>A(p.Gly2366Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,613,974 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (5 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.638

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=0.027032763).
• BP6: Variant 1-21851608-C-T is Benign according to our data. Variant chr1-21851608-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 447558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000946 (144/152262) while in subpopulation SAS AF= 0.00435 (21/4826). AF 95% confidence interval is 0.00292. There are 1 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.7096G>A	p.Gly2366Arg	missense_variant	55/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.7096G>A	p.Gly2366Arg	missense_variant	55/97	1	NM_005529.7	P1
HSPG2	ENST00000493940.2	n.305-18G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152144 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000780 AC: 196 AN: 251392 Hom.: 3 AF XY: 0.000934 AC XY: 127 AN XY: 135906

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00408

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000351 AC: 513 AN: 1461712 Hom.: 5 Cov.: 31 AF XY: 0.000473 AC XY: 344 AN XY: 727176

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00421

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000946 AC: 144 AN: 152262 Hom.: 1 Cov.: 33 AF XY: 0.000940 AC XY: 70 AN XY: 74456

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.000880

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000873 AC: 106

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 26, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 19, 2023	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HSPG2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2023

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.084
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.027	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	0.80	N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.76		Gain of MoRF binding (P = 0.0168);
MVP		0.77
MPC		0.36
ClinPred		0.060	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.62

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: rs140476180; hg19: chr1-22178101;