X-154032183-G-T
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_001110792.2(MECP2):c.413+24C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,159,120 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.0000089 ( 0 hom., 1 hem., cov: 24)
Exomes 𝑓: 0.000012 ( 0 hom. 3 hem. )
Consequence
MECP2
NM_001110792.2 intron
NM_001110792.2 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.42
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 -16 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
Variant X-154032183-G-T is Benign according to our data. Variant chrX-154032183-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 156055.Status of the report is reviewed_by_expert_panel, 3 stars.
BS2
?
High Hemizygotes in GnomAdExome at 2 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.413+24C>A | intron_variant | ENST00000453960.7 | |||
MECP2 | NM_004992.4 | c.377+24C>A | intron_variant | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000303391.11 | c.377+24C>A | intron_variant | 1 | NM_004992.4 | P1 | |||
MECP2 | ENST00000453960.7 | c.413+24C>A | intron_variant | 1 | NM_001110792.2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000885 AC: 1AN: 112978Hom.: 0 Cov.: 24 AF XY: 0.0000285 AC XY: 1AN XY: 35116
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GnomAD3 exomes AF: 0.0000438 AC: 8AN: 182455Hom.: 0 AF XY: 0.0000298 AC XY: 2AN XY: 67207
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GnomAD4 exome AF: 0.0000124 AC: 13AN: 1046142Hom.: 0 Cov.: 25 AF XY: 0.00000933 AC XY: 3AN XY: 321534
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:1Benign:3Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Rett syndrome Benign:2
Likely benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Oct 26, 2021 | The allele frequency of the c.377+24C>A variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.377+24C>A variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4). - |
Likely 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 likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in ExAC is between 0.008% and 0.03% (BS1). 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). - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Mar 10, 2010 | - - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jul 30, 2019 | - - |
not provided Other:1
not provided, flagged submission | literature only | RettBASE | - | - - |
Computational scores
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BayesDel_noAF
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at