1-21822499-C-G

Variant names:

• chr1-21822499-C-G
• rs549986026
• NM_005529.7:c.*817G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005529.7(HSPG2):​c.*817G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPG2 NM_005529.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 0 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]

LDLRAD2 (HGNC:32071): (low density lipoprotein receptor class A domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.*817G>C		3_prime_UTR	Exon 97 of 97	NP_005520.4
	LDLRAD2	NM_001013693.3	MANE Select	c.*284C>G		3_prime_UTR	Exon 5 of 5	NP_001013715.2	Q5SZI1
	HSPG2	NM_001291860.2		c.*817G>C		3_prime_UTR	Exon 97 of 97	NP_001278789.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.*817G>C		3_prime_UTR	Exon 97 of 97	ENSP00000363827.3	P98160
	LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*284C>G		3_prime_UTR	Exon 5 of 5	ENSP00000340988.2	Q5SZI1
	LDLRAD2	ENST00000543870.1	TSL:1	c.*218+66C>G		intron	N/A	ENSP00000444097.1	Q5SZI1

Frequencies

GnomAD3 genomes AF: 0.00000693 AC: 1 AN: 144240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000113 AC: 2 AN: 177044 Hom.: 0 Cov.: 0 AF XY: 0.0000104 AC XY: 1 AN XY: 96120

African (AFR) AF: 0.00 AC: 0 AN: 5146

American (AMR) AF: 0.00 AC: 0 AN: 10770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3998

East Asian (EAS) AF: 0.00 AC: 0 AN: 8470

South Asian (SAS) AF: 0.0000300 AC: 1 AN: 33304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 672

European-Non Finnish (NFE) AF: 0.0000102 AC: 1 AN: 97908

Other (OTH) AF: 0.00 AC: 0 AN: 8912

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000693 AC: 1 AN: 144380 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 1 AN XY: 70286

African (AFR) AF: 0.00 AC: 0 AN: 40062

American (AMR) AF: 0.00 AC: 0 AN: 14588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3366

East Asian (EAS) AF: 0.00 AC: 0 AN: 4254

South Asian (SAS) AF: 0.00 AC: 0 AN: 4030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65698

Other (OTH) AF: 0.00 AC: 0 AN: 2034

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.36
PhyloP100		0.0

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: rs549986026; hg19: chr1-22148992;