5-69534840-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_001205254.2(OCLN):c.1037+1G>A variant causes a splice donor change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000015 ( 0 hom., cov: 19)
Exomes 𝑓: 0.000020 ( 1 hom. )
Consequence
OCLN
NM_001205254.2 splice_donor
NM_001205254.2 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.56
Genes affected
OCLN (HGNC:8104): (occludin) This gene encodes an integral membrane protein that is required for cytokine-induced regulation of the tight junction paracellular permeability barrier. Mutations in this gene are thought to be a cause of band-like calcification with simplified gyration and polymicrogyria (BLC-PMG), an autosomal recessive neurologic disorder that is also known as pseudo-TORCH syndrome. Alternative splicing results in multiple transcript variants. A related pseudogene is present 1.5 Mb downstream on the q arm of chromosome 5. [provided by RefSeq, Apr 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 5-69534840-G-A is Pathogenic according to our data. Variant chr5-69534840-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 436101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-69534840-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OCLN | NM_001205254.2 | c.1037+1G>A | splice_donor_variant | ENST00000396442.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OCLN | ENST00000396442.7 | c.1037+1G>A | splice_donor_variant | 1 | NM_001205254.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000151 AC: 2AN: 132622Hom.: 0 Cov.: 19
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GnomAD3 exomes AF: 0.0000215 AC: 5AN: 232714Hom.: 1 AF XY: 0.0000316 AC XY: 4AN XY: 126528
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GnomAD4 exome AF: 0.0000200 AC: 25AN: 1251478Hom.: 1 Cov.: 19 AF XY: 0.0000286 AC XY: 18AN XY: 629984
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GnomAD4 genome AF: 0.0000151 AC: 2AN: 132622Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0AN XY: 64286
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pseudo-TORCH syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The homozygous c.1037+1G>A variant in OCLN was identified by our study in two siblings with intellectual disability and seizures (PMID: 35769956). The c.1037+1G>A variant in OCLN has been previously reported in one individual with pseudo-TORCH syndrome type 1 (PMID: 34374989) but has been identified in 0.01% (1/9210) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs748442113). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 436101) and has been interpreted as pathogenic by the University of Chicago Genetic Services Laboratory. The individual previously reported (PMID: 34374989) and the siblings identified by our study (PMID: 35769956) were homozygotes, which increases the likelihood that the c.1037+1G>A variant is pathogenic. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. Loss of function of the OCLN gene is an established disease mechanism in autosomal recessive pseudo-TORCH syndrome type 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive pseudo-TORCH syndrome type 1. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at