rs3027928
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001110792.2(MECP2):c.1269C>T(p.Ser423=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,204,764 control chromosomes in the GnomAD database, including 1,069 homozygotes. There are 3,208 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.018 ( 164 hom., 595 hem., cov: 22)
Exomes 𝑓: 0.0089 ( 905 hom. 2613 hem. )
Consequence
MECP2
NM_001110792.2 synonymous
NM_001110792.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.187
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BP6
?
Variant X-154030595-G-A is Benign according to our data. Variant chrX-154030595-G-A is described in ClinVar as [Benign]. Clinvar id is 95189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030595-G-A is described in Lovd as [Benign]. Variant chrX-154030595-G-A is described in Lovd as [Pathogenic].
BP7
?
Synonymous conserved (PhyloP=-0.187 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.1269C>T | p.Ser423= | synonymous_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.1233C>T | p.Ser411= | synonymous_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.1269C>T | p.Ser423= | synonymous_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.1233C>T | p.Ser411= | synonymous_variant | 4/4 | 1 | NM_004992.4 | P1 | |
MECP2 | ENST00000628176.2 | c.*605C>T | 3_prime_UTR_variant | 5/5 | 3 | ||||
MECP2 | ENST00000407218.5 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0181 AC: 1966AN: 108878Hom.: 159 Cov.: 22 AF XY: 0.0188 AC XY: 588AN XY: 31200
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GnomAD3 exomes AF: 0.0392 AC: 7070AN: 180207Hom.: 706 AF XY: 0.0278 AC XY: 1830AN XY: 65727
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GnomAD4 exome AF: 0.00891 AC: 9761AN: 1095840Hom.: 905 Cov.: 32 AF XY: 0.00722 AC XY: 2613AN XY: 362120
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GnomAD4 genome ? AF: 0.0182 AC: 1983AN: 108924Hom.: 164 Cov.: 22 AF XY: 0.0190 AC XY: 595AN XY: 31256
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ClinVar
Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 05, 2017 | - - |
Benign, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Jul 15, 2024 | This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 39. Only high quality variants are reported. - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 24, 2016 | Variant Summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico programs via Alamut predicting no significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2425/86448 (1/35 including 248 homozygotes and 583 hemizygotes), which significantly exceeds the predicted maximum expected allele frequency for a pathogenic MECP2 variant of 1/120481. In addition, multiple reputable database/clinical laboratories cite the variant with a classification of "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 04, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 09, 2021 | - - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Rett syndrome Benign:1
Benign, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Aug 14, 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). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). - |
History of neurodevelopmental disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2014 | This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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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