rs2254358

Variant names:

• chr1-21890081-C-A
• rs2254358
• NM_005529.7:c.474G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005529.7(HSPG2):​c.474G>T​(p.Gly158Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,613,166 control chromosomes in the GnomAD database, including 328,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23646 hom., cov: 31)
  • Exomes 𝑓: 0.64 (304544 hom.)
• Consequence: HSPG2 NM_005529.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.592
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• Schwartz-Jampel syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Schwartz-Jampel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.022).
• BP6: Variant 1-21890081-C-A is Benign according to our data. Variant chr1-21890081-C-A is described in ClinVar as Benign. ClinVar VariationId is 295910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.592 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005529.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.474G>T	p.Gly158Gly	synonymous	Exon 6 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.474G>T	p.Gly158Gly	synonymous	Exon 6 of 97	NP_001278789.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.474G>T	p.Gly158Gly	synonymous	Exon 6 of 97	ENSP00000363827.3
	HSPG2	ENST00000374673.4	TSL:3	c.228G>T	p.Gly76Gly	synonymous	Exon 3 of 7	ENSP00000497688.1
	HSPG2	ENST00000412328.5	TSL:2	n.242G>T		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80751 AN: 151752 Hom.: 23644 Cov.: 31

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.758

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.570

GnomAD2 exomes AF: 0.577 AC: 145150 AN: 251382 AF XY: 0.594

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.416

Gnomad ASJ exome AF: 0.747

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.666

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.640 AC: 934702 AN: 1461298 Hom.: 304544 Cov.: 50 AF XY: 0.641 AC XY: 466034 AN XY: 727006

African (AFR) AF: 0.286 AC: 9572 AN: 33470

American (AMR) AF: 0.425 AC: 19008 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 19612 AN: 26134

East Asian (EAS) AF: 0.406 AC: 16100 AN: 39694

South Asian (SAS) AF: 0.594 AC: 51197 AN: 86248

European-Finnish (FIN) AF: 0.635 AC: 33929 AN: 53408

Middle Eastern (MID) AF: 0.674 AC: 3882 AN: 5762

European-Non Finnish (NFE) AF: 0.669 AC: 743889 AN: 1111480

Other (OTH) AF: 0.621 AC: 37513 AN: 60384

GnomAD4 genome AF: 0.532 AC: 80763 AN: 151868 Hom.: 23646 Cov.: 31 AF XY: 0.530 AC XY: 39320 AN XY: 74198

African (AFR) AF: 0.294 AC: 12182 AN: 41400

American (AMR) AF: 0.483 AC: 7384 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.758 AC: 2626 AN: 3466

East Asian (EAS) AF: 0.369 AC: 1900 AN: 5146

South Asian (SAS) AF: 0.601 AC: 2892 AN: 4810

European-Finnish (FIN) AF: 0.644 AC: 6784 AN: 10540

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45110 AN: 67924

Other (OTH) AF: 0.572 AC: 1205 AN: 2106

Alfa AF: 0.621 Hom.: 123616

Bravo AF: 0.512

Asia WGS AF: 0.496 AC: 1724 AN: 3478

EpiCase AF: 0.675

EpiControl AF: 0.689

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Lethal Kniest-like syndrome (2)
-	-	2	Schwartz-Jampel syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.7
DANN	Uncertain	0.98
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2254358; hg19: chr1-22216574; COSMIC: COSV65930404; COSMIC: COSV65930404;