rs146950983

chr1-21850150-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BS1_Supporting

The NM_005529.7(HSPG2):c.7337C>T(p.Ser2446Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000808 in 1,613,428 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2446P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (2 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 B:2
• Conservation: PhyloP100: 6.12

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HSPG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.3165357).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000472 (72/152386) while in subpopulation NFE AF= 0.000838 (57/68040). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.7337C>T	p.Ser2446Leu	missense_variant	57/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.7337C>T	p.Ser2446Leu	missense_variant	57/97	1	NM_005529.7	P1

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152268 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000443 AC: 111 AN: 250538 Hom.: 0 AF XY: 0.000435 AC XY: 59 AN XY: 135656

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000866

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000843 AC: 1232 AN: 1461042 Hom.: 2 Cov.: 34 AF XY: 0.000820 AC XY: 596 AN XY: 726848

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000209

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000472 AC: 72 AN: 152386 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74514

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2021	The HSPG2 c.7337C>T; p.Ser2446Leu variant (rs146950983), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 290770). This variant is found in the general population with an overall allele frequency of 0.042% (118/281944 alleles) in the Genome Aggregation Database. The serine at codon 2446 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ser2446Leu variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2446 of the HSPG2 protein (p.Ser2446Leu). This variant is present in population databases (rs146950983, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 290770). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 08, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.080	N
MutationTaster	Benign	0.61	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Benign	0.28	T
Sift4G	Benign	0.072	T
Polyphen		0.97	D
Vest4		0.64
MVP		0.70
MPC		0.59
ClinPred		0.085	T
GERP RS		5.3
Varity_R		0.064
gMVP		0.32

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: rs146950983; hg19: chr1-22176643; COSMIC: COSV65970554; COSMIC: COSV65970554;