chr1-21822690-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.*626C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 166,772 control chromosomes in the GnomAD database, including 7,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7272 hom., cov: 29)

Exomes 𝑓: 0.23 ( 576 hom. )

Consequence

HSPG2
NM_005529.7 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.97

Variant links:

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 links:

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]

LDLRAD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

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

BP6

Variant 1-21822690-G-C is Benign according to our data. Variant chr1-21822690-G-C is described in ClinVar as [Benign]. Clinvar id is 295685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.*626C>G		3_prime_UTR_variant	Exon 97 of 97	ENST00000374695.8	NP_005520.4	P98160
LDLRAD2	NM_001013693.3 link	c.*475G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000344642.7	NP_001013715.2	Q5SZI1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695 link	c.*626C>G		3_prime_UTR_variant	Exon 97 of 97	1	NM_005529.7	ENSP00000363827.3		P98160
LDLRAD2	ENST00000344642.7 link	c.*475G>C		3_prime_UTR_variant	Exon 5 of 5	2	NM_001013693.3	ENSP00000340988.2		Q5SZI1

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45349

AN:

151464

Hom.:

7246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.407

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.302

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.404

Gnomad FIN

AF:

0.313

Gnomad MID

AF:

0.194

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.283

GnomAD4 exome

AF:

0.226

AC:

3439

AN:

15190

Hom.:

576

Cov.:

AF XY:

0.230

AC XY:

1881

AN XY:

8164

show subpopulations

Gnomad4 AFR exome

AF:

0.373

Gnomad4 AMR exome

AF:

0.164

Gnomad4 ASJ exome

AF:

0.269

Gnomad4 EAS exome

AF:

0.137

Gnomad4 SAS exome

AF:

0.332

Gnomad4 FIN exome

AF:

0.269

Gnomad4 NFE exome

AF:

0.220

Gnomad4 OTH exome

AF:

0.247

GnomAD4 genome

AF:

0.300

AC:

45424

AN:

151582

Hom.:

7272

Cov.:

AF XY:

0.299

AC XY:

22167

AN XY:

74046

show subpopulations

Gnomad4 AFR

AF:

0.407

Gnomad4 AMR

AF:

0.219

Gnomad4 ASJ

AF:

0.302

Gnomad4 EAS

AF:

0.167

Gnomad4 SAS

AF:

0.402

Gnomad4 FIN

AF:

0.313

Gnomad4 NFE

AF:

0.255

Gnomad4 OTH

AF:

0.284

Alfa

AF:

0.150

Hom.:

294

Bravo

AF:

0.294

Asia WGS

AF:

0.305

AC:

1060

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lethal Kniest-like syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Schwartz-Jampel syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.8

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over