rs267608424
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001110792.2(MECP2):c.143_149del(p.Lys48ArgfsTer87) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 24)
Consequence
MECP2
NM_001110792.2 frameshift
NM_001110792.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.61
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 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 346 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-154032470-CTCTTCTT-C is Pathogenic according to our data. Variant chrX-154032470-CTCTTCTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154032470-CTCTTCTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.143_149del | p.Lys48ArgfsTer87 | frameshift_variant | 2/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.107_113del | p.Lys36ArgfsTer87 | frameshift_variant | 3/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000303391.11 | c.107_113del | p.Lys36ArgfsTer87 | frameshift_variant | 3/4 | 1 | NM_004992.4 | P1 | |
MECP2 | ENST00000453960.7 | c.143_149del | p.Lys48ArgfsTer87 | frameshift_variant | 2/3 | 1 | NM_001110792.2 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | curation | RettBASE | Jan 21, 2008 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Oct 12, 2023 | 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 2.0, this variant is classified as likely pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 10, 2019 | Variant summary: MECP2 c.107_113delAAGAAGA (p.Lys36ArgfsX87) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 182010 control chromosomes (gnomAD). c.107_113delAAGAAGA has been reported in the literature in an individual affected with Rett Syndrome (Philippe_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg168*) have been determined to be pathogenic (PMID: 10577905, 11058114, 23270700, 24283265, 24511209). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 143324). This premature translational stop signal has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 16473305). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys36Argfs*87) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 451 amino acid(s) of the MECP2 protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at