rs267608564
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_001110792.2(MECP2):c.1105_1107del(p.Ser369del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S369S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 22)
Consequence
MECP2
NM_001110792.2 inframe_deletion
NM_001110792.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.09
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 Uncertain_significance. Variant got 1 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_001110792.2. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.1105_1107del | p.Ser369del | inframe_deletion | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.1069_1071del | p.Ser357del | inframe_deletion | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000303391.11 | c.1069_1071del | p.Ser357del | inframe_deletion | 4/4 | 1 | NM_004992.4 | P1 | |
MECP2 | ENST00000453960.7 | c.1105_1107del | p.Ser369del | inframe_deletion | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000407218.5 | c.*441_*443del | 3_prime_UTR_variant | 4/4 | 5 | ||||
MECP2 | ENST00000628176.2 | c.*441_*443del | 3_prime_UTR_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Mar 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 a variant of uncertain significance. 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). PMID17387578 This variant is absent from gnomAD (PM2_Supporting). Protein length changes of < 3 amino acid residues due to in-frame deletions/insertions in a non-repeat region (PM4_Supporting). - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Nov 01, 2007 | - - |
Severe neonatal-onset encephalopathy with microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2022 | Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 143320). This variant has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 17387578). This variant is not present in population databases (gnomAD no frequency). This variant, c.1069_1071del, results in the deletion of 1 amino acid(s) of the MECP2 protein (p.Ser357del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at