chrX-129545024-CAGATGTGTTCAAGGTACTAGCTTTAATTCCTTAGCTAGTTTTATAATGTTTTTTCTCGGTCATTACTGCATTATGTAATACCATACATATTTAAATTTGTCAGTGCATGTAAAATGAAATGTATTACTCTTTGCATAAAAAGATAACATTGAGGAGATGATACTTTCTCTAAGAATGCTGAAGGGTTATATCGAAATATATTTGTATATGTGTGTCTATAGTCTCACCTGTTTCCTTGGCTTGGGTTAGAGATGTATGTAGATTGTTACCTGTGTAGGTAGTTTTTTATGCTGACTGACCTATATGTGGATTTAAATAACATTCTTGGGCTTAACGGACACAGTGCTCATAAGGTACCAAGGTCACTTGGATTCACACACATTCAGCACTTTCTCCACATGCTATTTGAAATTAAGACATTTGGCAACATGCCTTGCCAGACTGTAATATCTTACACTCAAT-C

Variant names:

• chrX-129545024-CAGATGTGTTCAAGGTACTAGCTTTAATTCCTTAGCTAGTTTTATAATGTTTTTTCTCGGTCATTACTGCATTATGTAATACCATACATATTTAAATTTGTCAGTGCATGTAAAATGAAATGTATTACTCTTTGCATAAAAAGATAACATTGAGGAGATGATACTTTCTCTAAGAATGCTGAAGGGTTATATCGAAATATATTTGTATATGTGTGTCTATAGTCTCACCTGTTTCCTTGGCTTGGGTTAGAGATGTATGTAGATTGTTACCTGTGTAGGTAGTTTTTTATGCTGACTGACCTATATGTGGATTTAAATAACATTCTTGGGCTTAACGGACACAGTGCTCATAAGGTACCAAGGTCACTTGGATTCACACACATTCAGCACTTTCTCCACATGCTATTTGAAATTAAGACATTTGGCAACATGCCTTGCCAGACTGTAATATCTTACACTCAAT-C
• rs1556338810
• NM_000276.4:c.187_199+449del

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000276.4(OCRL):​c.187_199+449del​(p.Arg63GlyfsTer686) variant causes a frameshift, splice donor, splice region, intron change. 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 Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OCRL NM_000276.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.87
• Publications: 1 publications found

Genes affected

OCRL (HGNC:8108): (OCRL inositol polyphosphate-5-phosphatase) This gene encodes an inositol polyphosphate 5-phosphatase. This protein is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane. This protein may also play a role in primary cilium formation. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OCRL Gene-Disease associations (from GenCC):

• Dent disease type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-129545024-CAGATGTGTTCAAGGTACTAGCTTTAATTCCTTAGCTAGTTTTATAATGTTTTTTCTCGGTCATTACTGCATTATGTAATACCATACATATTTAAATTTGTCAGTGCATGTAAAATGAAATGTATTACTCTTTGCATAAAAAGATAACATTGAGGAGATGATACTTTCTCTAAGAATGCTGAAGGGTTATATCGAAATATATTTGTATATGTGTGTCTATAGTCTCACCTGTTTCCTTGGCTTGGGTTAGAGATGTATGTAGATTGTTACCTGTGTAGGTAGTTTTTTATGCTGACTGACCTATATGTGGATTTAAATAACATTCTTGGGCTTAACGGACACAGTGCTCATAAGGTACCAAGGTCACTTGGATTCACACACATTCAGCACTTTCTCCACATGCTATTTGAAATTAAGACATTTGGCAACATGCCTTGCCAGACTGTAATATCTTACACTCAAT-C is Pathogenic according to our data. Variant chrX-129545024-CAGATGTGTTCAAGGTACTAGCTTTAATTCCTTAGCTAGTTTTATAATGTTTTTTCTCGGTCATTACTGCATTATGTAATACCATACATATTTAAATTTGTCAGTGCATGTAAAATGAAATGTATTACTCTTTGCATAAAAAGATAACATTGAGGAGATGATACTTTCTCTAAGAATGCTGAAGGGTTATATCGAAATATATTTGTATATGTGTGTCTATAGTCTCACCTGTTTCCTTGGCTTGGGTTAGAGATGTATGTAGATTGTTACCTGTGTAGGTAGTTTTTTATGCTGACTGACCTATATGTGGATTTAAATAACATTCTTGGGCTTAACGGACACAGTGCTCATAAGGTACCAAGGTCACTTGGATTCACACACATTCAGCACTTTCTCCACATGCTATTTGAAATTAAGACATTTGGCAACATGCCTTGCCAGACTGTAATATCTTACACTCAAT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548654.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4	c.187_199+449del	p.Arg63GlyfsTer686	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.190_202+449del	p.Arg64GlyfsTer686	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 24		NP_001305713.1
OCRL	NM_001587.4	c.187_199+449del	p.Arg63GlyfsTer678	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.187_199+449del	p.Arg63GlyfsTer686	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 24	1	NM_000276.4	ENSP00000360154.4
OCRL	ENST00000357121.5	c.187_199+449del	p.Arg63GlyfsTer678	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 23	1		ENSP00000349635.5

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dent disease type 2 Pathogenic:1

Dec 08, 2016

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

Splicing

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

Other links and lift over

dbSNP: rs1556338810; hg19: chrX-128679001;