chr1-21880156-T-C

Variant names:

• chr1-21880156-T-C
• rs989994
• NM_005529.7:c.2294A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.2294A>G​(p.Asn765Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,614,162 control chromosomes in the GnomAD database, including 790,904 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67984 hom., cov: 35)
  • Exomes 𝑓: 0.99 (722920 hom.)
• Consequence: HSPG2 NM_005529.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.800
• Publications: 30 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Schwartz-Jampel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6722032E-6).
• BP6: Variant 1-21880156-T-C is Benign according to our data. Variant chr1-21880156-T-C is described in ClinVar as Benign. ClinVar VariationId is 295881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.2294A>G	p.Asn765Ser	missense	Exon 17 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.2297A>G	p.Asn766Ser	missense	Exon 17 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.2294A>G	p.Asn765Ser	missense	Exon 17 of 97	ENSP00000363827.3	P98160

Frequencies

GnomAD3 genomes AF: 0.940 AC: 143150 AN: 152252 Hom.: 67938 Cov.: 35

Gnomad AFR AF: 0.792

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.956

GnomAD2 exomes AF: 0.984 AC: 247466 AN: 251366 AF XY: 0.989

Gnomad AFR exome AF: 0.787

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.994 AC: 1453023 AN: 1461792 Hom.: 722920 Cov.: 63 AF XY: 0.995 AC XY: 723453 AN XY: 727210

African (AFR) AF: 0.792 AC: 26506 AN: 33478

American (AMR) AF: 0.988 AC: 44203 AN: 44722

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86224 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53350 AN: 53350

Middle Eastern (MID) AF: 0.994 AC: 5735 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111538 AN: 1111984

Other (OTH) AF: 0.987 AC: 59631 AN: 60396

GnomAD4 genome AF: 0.940 AC: 143248 AN: 152370 Hom.: 67984 Cov.: 35 AF XY: 0.942 AC XY: 70177 AN XY: 74518

African (AFR) AF: 0.792 AC: 32926 AN: 41568

American (AMR) AF: 0.978 AC: 14973 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5188

South Asian (SAS) AF: 0.999 AC: 4830 AN: 4834

European-Finnish (FIN) AF: 1.00 AC: 10632 AN: 10632

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 68001 AN: 68050

Other (OTH) AF: 0.957 AC: 2024 AN: 2116

Alfa AF: 0.974 Hom.: 156310

Bravo AF: 0.932

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.810 AC: 3571

ESP6500EA AF: 0.999 AC: 8592

ExAC AF: 0.981 AC: 119107

Asia WGS AF: 0.990 AC: 3443 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Lethal Kniest-like syndrome (2)
-	-	2	Schwartz-Jampel syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.80
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.25	T
Sift4G	Benign	0.16	T
Polyphen		0.0030	B
Vest4		0.049
MPC		0.17
ClinPred		0.017	T
GERP RS		5.4
Varity_R		0.091
gMVP		0.27
Mutation Taster		=96/4	polymorphism (auto)

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: rs989994; hg19: chr1-22206649; COSMIC: COSV107488376; COSMIC: COSV107488376;