rs3850326
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_001110792.2(MECP2):c.414-109A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,000,776 control chromosomes in the GnomAD database, including 793 homozygotes. There are 11,739 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.039 ( 77 hom., 1171 hem., cov: 23)
Exomes 𝑓: 0.044 ( 716 hom. 10568 hem. )
Consequence
MECP2
NM_001110792.2 intron
NM_001110792.2 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.795
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 -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.99).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0392 (4354/111086) while in subpopulation NFE AF= 0.0452 (2391/52912). AF 95% confidence interval is 0.0437. There are 77 homozygotes in gnomad4. There are 1171 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 77 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.414-109A>G | intron_variant | ENST00000453960.7 | |||
MECP2 | NM_004992.4 | c.378-109A>G | intron_variant | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000303391.11 | c.378-109A>G | intron_variant | 1 | NM_004992.4 | P1 | |||
MECP2 | ENST00000453960.7 | c.414-109A>G | intron_variant | 1 | NM_001110792.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0391 AC: 4338AN: 111035Hom.: 73 Cov.: 23 AF XY: 0.0351 AC XY: 1167AN XY: 33257
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GnomAD4 exome AF: 0.0437 AC: 38853AN: 889690Hom.: 716 AF XY: 0.0440 AC XY: 10568AN XY: 240348
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GnomAD4 genome ? AF: 0.0392 AC: 4354AN: 111086Hom.: 77 Cov.: 23 AF XY: 0.0351 AC XY: 1171AN XY: 33318
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ClinVar
Significance: Benign
Submissions summary: Benign:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:1Other:1
not provided, flagged submission | literature only | RettBASE | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
not specified Benign:1
Benign, no assertion criteria provided | curation | RettBASE | Dec 03, 2010 | - - |
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). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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