rs146309392
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_005529.7(HSPG2):c.7235G>A(p.Ser2412Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,612,062 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2412I) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00071 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0012 ( 3 hom. )
Consequence
HSPG2
NM_005529.7 missense
NM_005529.7 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 1.86
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HSPG2. . Gene score misZ 1.1367 (greater than the threshold 3.09). Trascript score misZ 3.3999 (greater than threshold 3.09). GenCC has associacion of gene with Silverman-Handmaker type dyssegmental dysplasia, Schwartz-Jampel syndrome type 1, Schwartz-Jampel syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.018512875).
BP6
Variant 1-21850422-C-T is Benign according to our data. Variant chr1-21850422-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290055.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000709 (108/152354) while in subpopulation NFE AF= 0.00125 (85/68034). AF 95% confidence interval is 0.00103. There are 1 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| HSPG2 | NM_005529.7 | c.7235G>A | p.Ser2412Asn | missense_variant | 56/97 | ENST00000374695.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HSPG2 | ENST00000374695.8 | c.7235G>A | p.Ser2412Asn | missense_variant | 56/97 | 1 | NM_005529.7 | P1 |
Frequencies
GnomAD3 genomes 0.000709 AC: 108AN: 152236Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000840 AC: 206AN: 245318Hom.: 1 AF XY: 0.000826 AC XY: 110AN XY: 133244
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GnomAD4 exome AF: 0.00123 AC: 1799AN: 1459708Hom.: 3 Cov.: 36 AF XY: 0.00122 AC XY: 887AN XY: 726054
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GnomAD4 genome 0.000709 AC: 108AN: 152354Hom.: 1 Cov.: 33 AF XY: 0.000671 AC XY: 50AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:5
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 14, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 31, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 27, 2020 | The HSPG2 c.7235G>A; p.Ser2412Asn variant (rs146309392), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 290055). This variant is found in the general population with an overall allele frequency of 0.08% (230/276708 alleles, including one homozygote) in the Genome Aggregation Database. The serine at codon 2412 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Ser2412Asn variant is uncertain at this time. - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The HSPG2 p.Ser2413Asn variant was not identified in the literature but was identified in dbSNP (ID: rs146309392), ClinVar (classified as uncertain significance by Illumina, Athena Diagnostics, EGL Clinical Diagnostics, and Fulgent Genetics), and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 230 of 276708 chromosomes (1 homozygous) at a frequency of 0.0008312 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 13 of 7082 chromosomes (freq: 0.001836), European (non-Finnish) in 181 of 125930 chromosomes (freq: 0.001437), Latino in 18 of 35024 chromosomes (freq: 0.000514), South Asian in 12 of 30202 chromosomes (freq: 0.000397) and African in 6 of 24384 chromosomes (freq: 0.000246), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. This frequency is greater than expected for the rare autosomal recessive Schwartz-Jampel syndrome condition and neonatal lethal Silverman-Handmaker dyssegmental dysplasia. The p.Ser2413 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 12, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | HSPG2: BP4, BS2 - |
Lethal Kniest-like syndrome Uncertain:1
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Schwartz-Jampel syndrome;C1857100:Lethal Kniest-like syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Schwartz-Jampel syndrome Uncertain:1
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at