chr1-21842308-T-C

Variant names:

• chr1-21842308-T-C
• rs2229491
• NM_005529.7:c.8983A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291860.2(HSPG2):​c.8986A>G​(p.Ser2996Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 1,613,086 control chromosomes in the GnomAD database, including 6,654 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2996S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (970 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5684 hom.)
• Consequence: HSPG2 NM_001291860.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.183
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016708672).
• BP6: Variant 1-21842308-T-C is Benign according to our data. Variant chr1-21842308-T-C is described in ClinVar as Benign. ClinVar VariationId is 295764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291860.2. 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.8983A>G	p.Ser2995Gly	missense	Exon 68 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.8986A>G	p.Ser2996Gly	missense	Exon 68 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.8983A>G	p.Ser2995Gly	missense	Exon 68 of 97	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15600 AN: 152158 Hom.: 968 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.0681

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0760 AC: 19020 AN: 250160 AF XY: 0.0778

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.0411

Gnomad ASJ exome AF: 0.0564

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0591

Gnomad NFE exome AF: 0.0794

Gnomad OTH exome AF: 0.0799

GnomAD4 exome AF: 0.0828 AC: 120980 AN: 1460810 Hom.: 5684 Cov.: 34 AF XY: 0.0837 AC XY: 60846 AN XY: 726612

African (AFR) AF: 0.192 AC: 6415 AN: 33466

American (AMR) AF: 0.0441 AC: 1969 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0564 AC: 1474 AN: 26124

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39692

South Asian (SAS) AF: 0.115 AC: 9937 AN: 86152

European-Finnish (FIN) AF: 0.0595 AC: 3147 AN: 52898

Middle Eastern (MID) AF: 0.101 AC: 580 AN: 5766

European-Non Finnish (NFE) AF: 0.0832 AC: 92456 AN: 1111698

Other (OTH) AF: 0.0827 AC: 4991 AN: 60368

GnomAD4 genome AF: 0.103 AC: 15622 AN: 152276 Hom.: 970 Cov.: 33 AF XY: 0.0982 AC XY: 7315 AN XY: 74466

African (AFR) AF: 0.178 AC: 7398 AN: 41556

American (AMR) AF: 0.0681 AC: 1042 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 185 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.109 AC: 527 AN: 4828

European-Finnish (FIN) AF: 0.0557 AC: 592 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0804 AC: 5469 AN: 68004

Other (OTH) AF: 0.106 AC: 225 AN: 2116

Alfa AF: 0.0859 Hom.: 1852

Bravo AF: 0.105

TwinsUK AF: 0.0930 AC: 345

ALSPAC AF: 0.0898 AC: 346

ESP6500AA AF: 0.181 AC: 799

ESP6500EA AF: 0.0767 AC: 660

ExAC AF: 0.0798 AC: 9687

Asia WGS AF: 0.0540 AC: 186 AN: 3478

EpiCase AF: 0.0776

EpiControl AF: 0.0755

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
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.1
DANN	Benign	0.27
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L
PhyloP100		-0.18
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.18
ClinPred		0.00020	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2229491; hg19: chr1-22168801;