10-98459735-C-G

Position:

• chr10-98459735-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021828.5(HPSE2):​c.1618G>C​(p.Val540Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00371 in 1,613,166 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: HPSE2 NM_021828.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.71

Genes affected

HPSE2 (HGNC:18374): (heparanase 2 (inactive)) This gene encodes a heparanase enzyme. The encoded protein is a endoglycosidase that degrades heparin sulfate proteoglycans located on the extracellular matrix and cell surface. This protein may be involved in biological processes involving remodeling of the extracellular matrix including angiogenesis and tumor progression. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011920303).
• BP6: Variant 10-98459735-C-G is Benign according to our data. Variant chr10-98459735-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 715582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00256 (390/152306) while in subpopulation NFE AF= 0.00445 (303/68032). AF 95% confidence interval is 0.00404. There are 1 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPSE2	NM_021828.5	c.1618G>C	p.Val540Leu	missense_variant	12/12	ENST00000370552.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPSE2	ENST00000370552.8	c.1618G>C	p.Val540Leu	missense_variant	12/12	1	NM_021828.5	P1

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 390 AN: 152188 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00445

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00340 AC: 842 AN: 247980 Hom.: 9 AF XY: 0.00362 AC XY: 487 AN XY: 134364

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00435

Gnomad FIN exome AF: 0.00309

Gnomad NFE exome AF: 0.00466

Gnomad OTH exome AF: 0.00481

GnomAD4 exome AF: 0.00383 AC: 5597 AN: 1460860 Hom.: 17 Cov.: 37 AF XY: 0.00378 AC XY: 2748 AN XY: 726608

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00420

Gnomad4 FIN exome AF: 0.00385

Gnomad4 NFE exome AF: 0.00417

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00256 AC: 390 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.00256 AC XY: 191 AN XY: 74476

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00445

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00311 Hom.: 0

Bravo AF: 0.00248

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00339 AC: 412

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	HPSE2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	0.0071	T
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Pathogenic	2.9	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	.;N;N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	.;D;D;.
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.98, 0.99	.;D;D;D
Vest4		0.72, 0.76
MutPred		0.69		.;Loss of sheet (P = 0.1158);.;.;
MVP		0.71
MPC		0.66
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.52
gMVP		0.74

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: rs140066668; hg19: chr10-100219492;