rs786205042
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_001110792.2(MECP2):c.47_57del(p.Gly16GlufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 20)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
MECP2
NM_001110792.2 frameshift
NM_001110792.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.19
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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. Fraction of 0.969 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PP5
Variant X-154097608-TCTCCTCCTCGC-T is Pathogenic according to our data. Variant chrX-154097608-TCTCCTCCTCGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 189770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154097608-TCTCCTCCTCGC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.47_57del | p.Gly16GlufsTer22 | frameshift_variant | 1/3 | ENST00000453960.7 | NP_001104262.1 | |
MECP2 | NM_004992.4 | c.-114_-104del | 5_prime_UTR_variant | 1/4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.47_57del | p.Gly16GlufsTer22 | frameshift_variant | 1/3 | 1 | NM_001110792.2 | ENSP00000395535 | ||
MECP2 | ENST00000303391.11 | c.-114_-104del | 5_prime_UTR_variant | 1/4 | 1 | NM_004992.4 | ENSP00000301948 | P1 |
Frequencies
GnomAD3 genomes Cov.: 20
GnomAD3 genomes
Cov.:
20
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 915109Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 280061
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
915109
Hom.:
AF XY:
AC XY:
0
AN XY:
280061
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 20
GnomAD4 genome
Cov.:
20
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:4
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 pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in>=4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). PMID: 15034579, 15689438 , 15857422, 17968969, 23810759 At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 15034579. This variant is absent from gnomAD (PM2_Supporting). - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 03, 2022 | The MECP2 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001110792.1, and corresponds to NM_004992.3:c.-114_-104del in the primary transcript. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189770). This variant is also known as c.38_48del11. This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 15857422, 16155192, 17968969, 22213695, 23810759). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly16Glufs*22) in the MECP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MECP2 are known to be pathogenic (PMID: 12180070). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at