rs61749711
Positions:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001110792.2(MECP2):c.618C>T(p.Ser206=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,209,931 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,176 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0020 ( 1 hom., 59 hem., cov: 23)
Exomes 𝑓: 0.0032 ( 4 hom. 1117 hem. )
Consequence
MECP2
NM_001110792.2 synonymous
NM_001110792.2 synonymous
Scores
2
9
Clinical Significance
Conservation
PhyloP100: -0.0860
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 (MetaRNN=0.008058667).
BP6
?
Variant X-154031246-G-A is Benign according to our data. Variant chrX-154031246-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031246-G-A is described in Lovd as [Likely_benign]. Variant chrX-154031246-G-A is described in Lovd as [Benign]. Variant chrX-154031246-G-A is described in Lovd as [Pathogenic].
BP7
?
Synonymous conserved (PhyloP=-0.086 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00195 (218/111719) while in subpopulation NFE AF= 0.00309 (164/53010). AF 95% confidence interval is 0.00271. There are 1 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd4 at 59 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.618C>T | p.Ser206= | synonymous_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.582C>T | p.Ser194= | synonymous_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.618C>T | p.Ser206= | synonymous_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.582C>T | p.Ser194= | synonymous_variant | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00195 AC: 218AN: 111669Hom.: 1 Cov.: 23 AF XY: 0.00174 AC XY: 59AN XY: 33861
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00230 AC: 421AN: 183308Hom.: 1 AF XY: 0.00233 AC XY: 158AN XY: 67812
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GnomAD4 exome AF: 0.00317 AC: 3484AN: 1098212Hom.: 4 Cov.: 35 AF XY: 0.00307 AC XY: 1117AN XY: 363574
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GnomAD4 genome ? AF: 0.00195 AC: 218AN: 111719Hom.: 1 Cov.: 23 AF XY: 0.00174 AC XY: 59AN XY: 33923
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 15, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Benign, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 09, 2012 | 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. - |
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Rett syndrome Benign:1
Benign, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Mar 22, 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 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 3.0 (BA1). - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
History of neurodevelopmental disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 01, 2016 | 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. - |
MECP2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 09, 2019 | 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;N
Sift4G
Uncertain
T;T
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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