rs786205049
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePP3_ModeratePP5_Very_Strong
The NM_001110792.2(MECP2):c.62+2_62+3del variant causes a splice donor, splice donor region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 20)
Consequence
MECP2
NM_001110792.2 splice_donor, splice_donor_region, intron
NM_001110792.2 splice_donor, splice_donor_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.54
Genes affected
MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.075484306 fraction of the gene.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant X-154097600-TCA-T is Pathogenic according to our data. Variant chrX-154097600-TCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154097600-TCA-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154097600-TCA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.62+2_62+3del | splice_donor_variant, splice_donor_region_variant, intron_variant | ENST00000453960.7 | |||
MECP2 | NM_004992.4 | c.-99+2_-99+3del | splice_donor_variant, splice_donor_region_variant, intron_variant | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000303391.11 | c.-99+2_-99+3del | splice_donor_variant, splice_donor_region_variant, intron_variant | 1 | NM_004992.4 | P1 | |||
MECP2 | ENST00000453960.7 | c.62+2_62+3del | splice_donor_variant, splice_donor_region_variant, intron_variant | 1 | NM_001110792.2 |
Frequencies
GnomAD3 genomes Cov.: 20
GnomAD3 genomes
Cov.:
20
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 20
GnomAD4 genome
Cov.:
20
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Feb 18, 2024 | This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely pathogenic. At least the following criteria are met:At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 16829352 The computational splicing predictor SpliceAI support a splicing alteration (score of >0.2) (DL 0.99, DG 0.32) (PP3).This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). PMID 19365833, 15689438, ClinVar; [VCV000189777.21], This variant is absent from gnomAD (PM2_Supporting). - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Nov 05, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics | - | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jan 05, 2022 | ACMG categories: PVS1,PM2,PP3,PP5 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
DS_DL_spliceai
Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at