1-21850150-G-A

Position:

chr1-21850150-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5B:2

Conservation

PhyloP100: 6.12

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 Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HSPG2. . Gene score misZ 1.1367 (greater than the threshold 3.09). Trascript score misZ 3.3999 (greater than threshold 3.09). GenCC has associacion of gene with Silverman-Handmaker type dyssegmental dysplasia, Schwartz-Jampel syndrome type 1, Schwartz-Jampel syndrome.

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. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	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 linkuse as main transcript	c.7337C>T	p.Ser2446Leu	missense_variant	57/97	1	NM_005529.7	P1

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000435

AC XY:

AN XY:

135656

show subpopulations

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.:

Cov.:

AF XY:

0.000820

AC XY:

596

AN XY:

726848

show subpopulations

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:

AN:

152386

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74514

show subpopulations

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.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

M_CAP

Benign

0.036

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.080

MutationTaster

Benign

0.61

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.1

REVEL

Benign

0.23

Sift

Benign

0.28

Sift4G

Benign

0.072

Polyphen

0.97

Vest4

0.64

MVP

0.70

MPC

0.59

ClinPred

0.085

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

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