chrX-154030358-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001110792.2(MECP2):c.*9G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000794 in 1,209,801 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 305 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 0.00080 ( 0 hom., 36 hem., cov: 23)
Exomes 𝑓: 0.00079 ( 0 hom. 269 hem. )
Consequence
MECP2
NM_001110792.2 3_prime_UTR
NM_001110792.2 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.574
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
Variant X-154030358-C-T is Benign according to our data. Variant chrX-154030358-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 143298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030358-C-T is described in Lovd as [Likely_benign]. Variant chrX-154030358-C-T is described in Lovd as [Benign]. Variant chrX-154030358-C-T is described in Lovd as [Pathogenic].
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000798 (89/111598) while in subpopulation EAS AF= 0.00253 (9/3553). AF 95% confidence interval is 0.00132. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd at 36 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.*9G>A | 3_prime_UTR_variant | 3/3 | ENST00000453960.7 | ||
MECP2 | NM_004992.4 | c.*9G>A | 3_prime_UTR_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000303391.11 | c.*9G>A | 3_prime_UTR_variant | 4/4 | 1 | NM_004992.4 | P1 | ||
MECP2 | ENST00000453960.7 | c.*9G>A | 3_prime_UTR_variant | 3/3 | 1 | NM_001110792.2 | |||
MECP2 | ENST00000628176.2 | c.*842G>A | 3_prime_UTR_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000789 AC: 88AN: 111544Hom.: 0 Cov.: 23 AF XY: 0.00107 AC XY: 36AN XY: 33712
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GnomAD3 exomes AF: 0.000741 AC: 136AN: 183447Hom.: 0 AF XY: 0.000633 AC XY: 43AN XY: 67881
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GnomAD4 exome AF: 0.000794 AC: 872AN: 1098203Hom.: 0 Cov.: 32 AF XY: 0.000740 AC XY: 269AN XY: 363557
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | curation | RettBASE | Aug 24, 2010 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 08, 2014 | - - |
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 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). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2) - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
History of neurodevelopmental disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2013 | 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 | Jul 02, 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
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at