chr1-21879108-T-C

Variant names:

• chr1-21879108-T-C
• rs143736974
• NM_005529.7:c.2357A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005529.7(HSPG2):​c.2357A>G​(p.Asn786Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00694 in 1,614,212 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0061 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (58 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 5.19
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012245119).
• BP6: Variant 1-21879108-T-C is Benign according to our data. Variant chr1-21879108-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209161.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00607 (924/152340) while in subpopulation NFE AF = 0.00867 (590/68042). AF 95% confidence interval is 0.00809. There are 5 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.2357A>G	p.Asn786Ser	missense_variant	Exon 18 of 97	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.2357A>G	p.Asn786Ser	missense_variant	Exon 18 of 97	1	NM_005529.7	ENSP00000363827.3
HSPG2	ENST00000480900.1	n.-34A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 923 AN: 152222 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00621 AC: 1561 AN: 251436 AF XY: 0.00659

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00826

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00703 AC: 10283 AN: 1461872 Hom.: 58 Cov.: 35 AF XY: 0.00709 AC XY: 5156 AN XY: 727240

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00228 AC: 102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00765 AC: 200 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00289 AC: 249 AN: 86258

European-Finnish (FIN) AF: 0.0159 AC: 850 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00758 AC: 8432 AN: 1112000

Other (OTH) AF: 0.00677 AC: 409 AN: 60394

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152340 Hom.: 5 Cov.: 33 AF XY: 0.00611 AC XY: 455 AN XY: 74488

African (AFR) AF: 0.00127 AC: 53 AN: 41578

American (AMR) AF: 0.00458 AC: 70 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00867 AC: 590 AN: 68042

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00698 Hom.: 20

Bravo AF: 0.00457

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00666 AC: 808

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HSPG2: BP4, BS2 -

Feb 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25504735) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Schwartz-Jampel syndrome Uncertain:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jul 30, 2015

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been seen once in our laboratory in trans with another variant [T1639M] in a 37-year-old female with adult-onset myalgia, myotonia, intractable pain, stiffness, weakness, constipation. However, other individuals in our lab with this variant and additional HSPG2 variants (phase undetermined) have not had significant overlap with the syndrome, although if it predisposes to a milder adult-onset version, they may be too young for symptoms. -

not specified Benign:1

Dec 29, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal Kniest-like syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Connective tissue disorder Benign:1

Aug 19, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.38
Sift	Benign	0.25	T
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.61
MPC		0.18
ClinPred		0.057	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.28
Mutation Taster		=80/20	polymorphism

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: rs143736974; hg19: chr1-22205601; COSMIC: COSV104687789; COSMIC: COSV104687789;