1-21857246-A-G

Variant names:

• chr1-21857246-A-G
• rs2305562
• NM_005529.7:c.5394+39T>C

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.5394+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,613,468 control chromosomes in the GnomAD database, including 221,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19234 hom., cov: 31)
  • Exomes 𝑓: 0.52 (202578 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.67
• Publications: 12 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 (BayesDel_noAF=-0.77).
• BP6: Variant 1-21857246-A-G is Benign according to our data. Variant chr1-21857246-A-G is described in ClinVar as Benign. ClinVar VariationId is 1220862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.543 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.5394+39T>C		intron	N/A	NP_005520.4
	HSPG2	NM_001291860.2		c.5397+39T>C		intron	N/A	NP_001278789.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.5394+39T>C		intron	N/A	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75916 AN: 151812 Hom.: 19217 Cov.: 31

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.519

GnomAD2 exomes AF: 0.504 AC: 126636 AN: 251246 AF XY: 0.503

Gnomad AFR exome AF: 0.420

Gnomad AMR exome AF: 0.484

Gnomad ASJ exome AF: 0.588

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.546

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.524 AC: 766130 AN: 1461538 Hom.: 202578 Cov.: 42 AF XY: 0.522 AC XY: 379589 AN XY: 727066

African (AFR) AF: 0.425 AC: 14222 AN: 33476

American (AMR) AF: 0.482 AC: 21573 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 15262 AN: 26134

East Asian (EAS) AF: 0.487 AC: 19335 AN: 39698

South Asian (SAS) AF: 0.386 AC: 33304 AN: 86244

European-Finnish (FIN) AF: 0.545 AC: 29083 AN: 53366

Middle Eastern (MID) AF: 0.588 AC: 3391 AN: 5768

European-Non Finnish (NFE) AF: 0.538 AC: 598667 AN: 1111740

Other (OTH) AF: 0.518 AC: 31293 AN: 60392

GnomAD4 genome AF: 0.500 AC: 75984 AN: 151930 Hom.: 19234 Cov.: 31 AF XY: 0.499 AC XY: 37017 AN XY: 74224

African (AFR) AF: 0.428 AC: 17726 AN: 41410

American (AMR) AF: 0.480 AC: 7329 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2035 AN: 3470

East Asian (EAS) AF: 0.460 AC: 2369 AN: 5152

South Asian (SAS) AF: 0.375 AC: 1806 AN: 4816

European-Finnish (FIN) AF: 0.547 AC: 5782 AN: 10580

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37230 AN: 67918

Other (OTH) AF: 0.517 AC: 1092 AN: 2112

Alfa AF: 0.542 Hom.: 33863

Bravo AF: 0.496

Asia WGS AF: 0.435 AC: 1512 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.74
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2305562; hg19: chr1-22183739; COSMIC: COSV65970004; COSMIC: COSV65970004;