1-21822690-G-C

Position:

• chr1-21822690-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.97

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
LDLRAD2	NM_001013693.3	c.*475G>C		3_prime_UTR_variant	5/5	ENST00000344642.7
HSPG2	NM_005529.7	c.*626C>G		3_prime_UTR_variant	97/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLRAD2	ENST00000344642.7	c.*475G>C		3_prime_UTR_variant	5/5	2	NM_001013693.3	P1
HSPG2	ENST00000374695.8	c.*626C>G		3_prime_UTR_variant	97/97	1	NM_005529.7	P1
LDLRAD2	ENST00000543870.1	c.*218+257G>C		intron_variant		1		P1
HSPG2	ENST00000486901.1	n.3141C>G		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45349 AN: 151464 Hom.: 7246 Cov.: 29

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.: 0 AF XY: 0.230 AC XY: 1881 AN XY: 8164

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.: 29 AF XY: 0.299 AC XY: 22167 AN XY: 74046

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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal Kniest-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

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

Other links and lift over

dbSNP: rs1049644; hg19: chr1-22149183; COSMIC: COSV60827857; COSMIC: COSV60827857;