rs2270701

Variant names:

• chr1-21831627-G-T
• rs2270701
• NM_005529.7:c.11352+25C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21831627-G-T
• chr1-21831627-G-A

Variant summary

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

The NM_005529.7(HSPG2):​c.11352+25C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,610,728 control chromosomes in the GnomAD database, including 28,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1896 hom., cov: 33)
  • Exomes 𝑓: 0.18 (26298 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.50
• Publications: 10 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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 (BayesDel_noAF=-0.92).
• BP6: Variant 1-21831627-G-T is Benign according to our data. Variant chr1-21831627-G-T is described in ClinVar as Benign. ClinVar VariationId is 1261831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.11352+25C>A		intron	N/A	NP_005520.4
	HSPG2	NM_001291860.2		c.11355+25C>A		intron	N/A	NP_001278789.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.11352+25C>A		intron	N/A	ENSP00000363827.3	P98160
	HSPG2	ENST00000635682.1	TSL:5	c.501+25C>A		intron	N/A	ENSP00000489161.1	A0A0U1RQT3

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22287 AN: 152046 Hom.: 1894 Cov.: 33

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.181 AC: 44064 AN: 243214 AF XY: 0.190

Gnomad AFR exome AF: 0.0590

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.185 AC: 269771 AN: 1458564 Hom.: 26298 Cov.: 36 AF XY: 0.188 AC XY: 136338 AN XY: 725388

African (AFR) AF: 0.0573 AC: 1918 AN: 33462

American (AMR) AF: 0.128 AC: 5603 AN: 43916

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5037 AN: 26006

East Asian (EAS) AF: 0.171 AC: 6771 AN: 39592

South Asian (SAS) AF: 0.283 AC: 24273 AN: 85896

European-Finnish (FIN) AF: 0.235 AC: 12505 AN: 53254

Middle Eastern (MID) AF: 0.133 AC: 764 AN: 5764

European-Non Finnish (NFE) AF: 0.182 AC: 201909 AN: 1110392

Other (OTH) AF: 0.182 AC: 10991 AN: 60282

GnomAD4 genome AF: 0.147 AC: 22298 AN: 152164 Hom.: 1896 Cov.: 33 AF XY: 0.150 AC XY: 11131 AN XY: 74380

African (AFR) AF: 0.0590 AC: 2450 AN: 41552

American (AMR) AF: 0.130 AC: 1985 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 678 AN: 3470

East Asian (EAS) AF: 0.166 AC: 854 AN: 5158

South Asian (SAS) AF: 0.299 AC: 1441 AN: 4824

European-Finnish (FIN) AF: 0.241 AC: 2548 AN: 10590

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11933 AN: 67958

Other (OTH) AF: 0.143 AC: 302 AN: 2114

Alfa AF: 0.158 Hom.: 2191

Bravo AF: 0.134

Asia WGS AF: 0.240 AC: 835 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Lethal Kniest-like syndrome (1)
-	-	1	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.023
DANN	Benign	0.45
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2270701;

hg19: chr1-22158120;