X-132628623-A-G

Variant names:

• chrX-132628623-A-G
• rs1190798652
• NM_001394073.1:c.1538T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001394073.1(HS6ST2):​c.1538T>C​(p.Ile513Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,209,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 8 hem.)
• Consequence: HS6ST2 NM_001394073.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 1 publications found

Genes affected

HS6ST2 (HGNC:19133): (heparan sulfate 6-O-sulfotransferase 2) Heparan sulfate proteoglycans are ubiquitous components of the cell surface, extracellular matrix, and basement membranes, and interact with various ligands to influence cell growth, differentiation, adhesion, and migration. This gene encodes a member of the heparan sulfate (HS) sulfotransferase gene family, which catalyze the transfer of sulfate to HS. Different family members and isoforms are thought to synthesize heparan sulfates with tissue-specific structures and functions. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HS6ST2 Gene-Disease associations (from GenCC):

• Paganini-Miozzo syndrome

  Inheritance: Unknown, XL Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000296977 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0563069).
• BS2: High Hemizygotes in GnomAdExome4 at 8 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394073.1. 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
	HS6ST2	NM_001394073.1	MANE Select	c.1538T>C	p.Ile513Thr	missense	Exon 5 of 5	NP_001381002.1	Q96MM7-4
	HS6ST2	NM_001077188.2		c.1538T>C	p.Ile513Thr	missense	Exon 6 of 6	NP_001070656.1	Q96MM7-4
	HS6ST2	NM_001394074.1		c.1418T>C	p.Ile473Thr	missense	Exon 3 of 3	NP_001381003.1	Q96MM7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HS6ST2	ENST00000370833.7	TSL:5 MANE Select	c.1538T>C	p.Ile513Thr	missense	Exon 5 of 5	ENSP00000359870.3	Q96MM7-4
	HS6ST2	ENST00000406696.5	TSL:1	c.1100T>C	p.Ile367Thr	missense	Exon 5 of 5	ENSP00000384013.5	Q96MM7-3
	HS6ST2	ENST00000521489.5	TSL:5	c.1538T>C	p.Ile513Thr	missense	Exon 6 of 6	ENSP00000429473.1	Q96MM7-4

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111182 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000383

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181086 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1097998 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 8 AN XY: 363458

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841936

Other (OTH) AF: 0.0000651 AC: 3 AN: 46074

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111182 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33460

African (AFR) AF: 0.00 AC: 0 AN: 30539

American (AMR) AF: 0.00 AC: 0 AN: 10446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3532

South Asian (SAS) AF: 0.000383 AC: 1 AN: 2612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53001

Other (OTH) AF: 0.00 AC: 0 AN: 1478

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.2
DANN	Benign	0.51
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.093
Sift	Benign	0.47	T
Sift4G	Benign	0.93	T
Polyphen		0.14	B
Vest4		0.062
MutPred		0.38		Gain of sheet (P = 0.0344)
MVP		0.84
MPC		0.77
ClinPred		0.058	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.36
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1190798652; hg19: chrX-131762651;