NM_001394073.1:c.1742C>T

Variant names:

• chrX-132628419-G-A
• rs367714566
• NM_001394073.1:c.1742C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001394073.1(HS6ST2):​c.1742C>T​(p.Pro581Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 1,202,292 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000064 (0 hom. 2 hem.)
• Consequence: HS6ST2 NM_001394073.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.991
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07226461).
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.1742C>T	p.Pro581Leu	missense	Exon 5 of 5	NP_001381002.1	Q96MM7-4
	HS6ST2	NM_001077188.2		c.1742C>T	p.Pro581Leu	missense	Exon 6 of 6	NP_001070656.1	Q96MM7-4
	HS6ST2	NM_001394074.1		c.1622C>T	p.Pro541Leu	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.1742C>T	p.Pro581Leu	missense	Exon 5 of 5	ENSP00000359870.3	Q96MM7-4
	HS6ST2	ENST00000406696.5	TSL:1	c.1304C>T	p.Pro435Leu	missense	Exon 5 of 5	ENSP00000384013.5	Q96MM7-3
	HS6ST2	ENST00000521489.5	TSL:5	c.1742C>T	p.Pro581Leu	missense	Exon 6 of 6	ENSP00000429473.1	Q96MM7-4

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110904 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000641 AC: 7 AN: 1091388 Hom.: 0 Cov.: 29 AF XY: 0.00000559 AC XY: 2 AN XY: 357534

African (AFR) AF: 0.0000761 AC: 2 AN: 26286

American (AMR) AF: 0.00 AC: 0 AN: 34857

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19327

East Asian (EAS) AF: 0.00 AC: 0 AN: 30030

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53882

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40421

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00000359 AC: 3 AN: 836604

Other (OTH) AF: 0.00 AC: 0 AN: 45860

GnomAD4 genome AF: 0.00000902 AC: 1 AN: 110904 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33130

African (AFR) AF: 0.0000329 AC: 1 AN: 30379

American (AMR) AF: 0.00 AC: 0 AN: 10413

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2577

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53013

Other (OTH) AF: 0.00 AC: 0 AN: 1485

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.70
DANN	Benign	0.49
DEOGEN2	Benign	0.099	T
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.99
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.084	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.0	B
Vest4		0.11
MVP		0.79
MPC		0.62
ClinPred		0.036	T
GERP RS		-3.0
Varity_R		0.030
gMVP		0.60
Mutation Taster		=94/6	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: rs367714566; hg19: chrX-131762447; COSMIC: COSV63710902; COSMIC: COSV63710902;