rs61751446
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.978C>T(p.Ile326=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,210,814 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 146 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 0.00036 ( 0 hom., 14 hem., cov: 23)
Exomes 𝑓: 0.00034 ( 0 hom. 132 hem. )
Consequence
MECP2
NM_001110792.2 synonymous
NM_001110792.2 synonymous
Scores
5
Clinical Significance
Conservation
PhyloP100: -0.216
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_addAF=-0.498445).
BP6
?
Variant X-154030886-G-A is Benign according to our data. Variant chrX-154030886-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030886-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.216 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000355 (40/112566) while in subpopulation EAS AF= 0.0014 (5/3578). AF 95% confidence interval is 0.000574. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd4 at 14 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.978C>T | p.Ile326= | synonymous_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.942C>T | p.Ile314= | synonymous_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.978C>T | p.Ile326= | synonymous_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.942C>T | p.Ile314= | synonymous_variant | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000356 AC: 40AN: 112515Hom.: 0 Cov.: 23 AF XY: 0.000404 AC XY: 14AN XY: 34663
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GnomAD3 exomes AF: 0.000398 AC: 73AN: 183500Hom.: 0 AF XY: 0.000397 AC XY: 27AN XY: 67934
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GnomAD4 exome AF: 0.000342 AC: 376AN: 1098248Hom.: 0 Cov.: 35 AF XY: 0.000363 AC XY: 132AN XY: 363602
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GnomAD4 genome ? AF: 0.000355 AC: 40AN: 112566Hom.: 0 Cov.: 23 AF XY: 0.000403 AC XY: 14AN XY: 34724
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | curation | RettBASE | Mar 29, 2011 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 04, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 22, 2017 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 20, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | MECP2: BP4, BP7 - |
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). - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 19, 2022 | - - |
History of neurodevelopmental disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2017 | General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D;D
Vest4
GERP RS
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