chrX-149505100-AGCCAGAGAAGGCCTCG-A

Variant names:

• chrX-149505100-AGCCAGAGAAGGCCTCG-A
• rs864622775
• NM_000202.8:c.22_37delCGAGGCCTTCTCTGGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000202.8(IDS):​c.22_37delCGAGGCCTTCTCTGGC​(p.Arg8TrpfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R8R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IDS NM_000202.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.74
• Publications: 1 publications found

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

ENSG00000241489 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 739 pathogenic variants in the truncated region.
• PP5: Variant X-149505100-AGCCAGAGAAGGCCTCG-A is Pathogenic according to our data. Variant chrX-149505100-AGCCAGAGAAGGCCTCG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 221215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.22_37delCGAGGCCTTCTCTGGC	p.Arg8TrpfsTer5	frameshift_variant	Exon 1 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_006123.5	c.22_37delCGAGGCCTTCTCTGGC	p.Arg8TrpfsTer5	frameshift_variant	Exon 1 of 8		NP_006114.1
IDS	NR_104128.2	n.191_206delCGAGGCCTTCTCTGGC		non_coding_transcript_exon_variant	Exon 1 of 9
IDS	NM_001166550.4	c.-205_-190delCGAGGCCTTCTCTGGC		5_prime_UTR_variant	Exon 1 of 9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.22_37delCGAGGCCTTCTCTGGC	p.Arg8TrpfsTer5	frameshift_variant	Exon 1 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.-215-4079_-215-4064delCGAGGCCTTCTCTGGC		intron_variant	Intron 8 of 13			ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:2

May 16, 2012

IIFP, CONICET-UNLP

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 07, 2024

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Null variant (PVS1_VeryStrong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864622775; hg19: chrX-148586630;