rs145476116

chr1-21880124-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.2326G>A(p.Val776Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,614,106 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.53

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=0.010389894).
• BP6: Variant 1-21880124-C-T is Benign according to our data. Variant chr1-21880124-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00168 (256/152388) while in subpopulation AFR AF= 0.00572 (238/41602). AF 95% confidence interval is 0.00512. There are 0 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.2326G>A	p.Val776Met	missense_variant	17/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.2326G>A	p.Val776Met	missense_variant	17/97	1	NM_005529.7	P1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152270 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00574

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000513 AC: 129 AN: 251356 Hom.: 2 AF XY: 0.000405 AC XY: 55 AN XY: 135892

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000177 AC: 259 AN: 1461718 Hom.: 3 Cov.: 30 AF XY: 0.000147 AC XY: 107 AN XY: 727164

Gnomad4 AFR exome AF: 0.00681

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152388 Hom.: 0 Cov.: 34 AF XY: 0.00162 AC XY: 121 AN XY: 74526

Gnomad4 AFR AF: 0.00572

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.00210

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000618 AC: 75

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	HSPG2: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 15, 2016	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.37
MVP		0.66
MPC		0.64
ClinPred		0.031	T
GERP RS		5.4
Varity_R		0.17
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: rs145476116; hg19: chr1-22206617;