rs1557150846
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001110792.2(MECP2):c.57_58insGAGGAGGCGAGGAGGAG(p.Arg20GlufsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 20)
Consequence
MECP2
NM_001110792.2 frameshift
NM_001110792.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.73
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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 371 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-154097608-T-TCTCCTCCTCGCCTCCTC is Pathogenic according to our data. Variant chrX-154097608-T-TCTCCTCCTCGCCTCCTC is described in ClinVar as [Pathogenic]. Clinvar id is 406153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.57_58insGAGGAGGCGAGGAGGAG | p.Arg20GlufsTer30 | frameshift_variant | 1/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.-104_-103insGAGGAGGCGAGGAGGAG | 5_prime_UTR_variant | 1/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.57_58insGAGGAGGCGAGGAGGAG | p.Arg20GlufsTer30 | frameshift_variant | 1/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.-104_-103insGAGGAGGCGAGGAGGAG | 5_prime_UTR_variant | 1/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 20
GnomAD3 genomes
Cov.:
20
GnomAD4 exome Cov.: 26
GnomAD4 exome
Cov.:
26
GnomAD4 genome Cov.: 20
GnomAD4 genome
Cov.:
20
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MECP2 are known to be pathogenic (PMID: 12180070). This variant has been reported to be de novo in an individual affected with Rett syndrome (PMID: 27171548). This variant is not present in population databases (ExAC no frequency). This sequence change inserts 17 nucleotides in exon 1 of the MECP2 mRNA (NM_001110792.1:c.41_57dup), causing a frameshift at codon 20. This creates a premature translational stop signal (p.Arg20Glufs*30) and is expected to result in an absent or disrupted protein product. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27171548) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at