Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000202.8(IDS):c.1505G>C(p.Trp502Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W502G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.90

Publications

4 publications found

Variant links:

Genes affected

IDS (HGNC:5389): (iduronate 2-sulfatase) This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

IDS Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 2
Inheritance: XL, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia, Myriad Women’s Health
mucopolysaccharidosis type 2, attenuated form
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
mucopolysaccharidosis type 2, severe form
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

IDS links:

ENSG00000241489 (HGNC:):

ENSG00000241489 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000202.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-149482895-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 977228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant X-149482894-C-G is Pathogenic according to our data. Variant chrX-149482894-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 10488.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000202.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	NM_000202.8	MANE Select	c.1505G>C	p.Trp502Ser	missense	Exon 9 of 9	NP_000193.1
	IDS	NM_001166550.4		c.1235G>C	p.Trp412Ser	missense	Exon 9 of 9	NP_001160022.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IDS	ENST00000340855.11	TSL:1 MANE Select	c.1505G>C	p.Trp502Ser	missense	Exon 9 of 9	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1		c.872G>C	p.Trp291Ser	missense	Exon 14 of 14	ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	TSL:2	c.872G>C	p.Trp291Ser	missense	Exon 9 of 9	ENSP00000477056.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis, MPS-II (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.72

BayesDel_noAF

Pathogenic

0.79

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.6

PhyloP100

6.9

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-13

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MutPred

0.96

Gain of sheet (P = 0.0344)

MVP

1.0

MPC

1.0

ClinPred

1.0

GERP RS

5.4

Varity_R

0.99

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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rs199422228

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over