Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001316337.2(MECP2):c.-70C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,211,438 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 121 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
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]
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant X-154032374-G-A is Benign according to our data. Variant chrX-154032374-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154032374-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00109 (124/113349) while in subpopulation AFR AF= 0.00322 (101/31341). AF 95% confidence interval is 0.00271. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Oct 12, 2016
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Rett syndrome Benign:1
Benign, 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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). -
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 29, 2024
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Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Nov 12, 2021
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History of neurodevelopmental disorder Benign:1
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jan 17, 2017
General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -
MECP2-related disorder Benign:1
Likely benign, no assertion criteria provided
clinical testing
PreventionGenetics, part of Exact Sciences
May 21, 2021
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -