rs782027467
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_001110792.2(MECP2):c.771C>G(p.Val257=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,098,212 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.000031 ( 0 hom. 10 hem. )
Consequence
MECP2
NM_001110792.2 synonymous
NM_001110792.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.584
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 -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
?
Variant X-154031093-G-C is Benign according to our data. Variant chrX-154031093-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 413770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.584 with no splicing effect.
BS2
?
High Hemizygotes in GnomAdExome at 6 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.771C>G | p.Val257= | synonymous_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.735C>G | p.Val245= | synonymous_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.771C>G | p.Val257= | synonymous_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.735C>G | p.Val245= | synonymous_variant | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
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?
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23
GnomAD3 exomes AF: 0.000131 AC: 24AN: 183217Hom.: 0 AF XY: 0.0000886 AC XY: 6AN XY: 67745
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GnomAD4 exome AF: 0.0000310 AC: 34AN: 1098212Hom.: 0 Cov.: 36 AF XY: 0.0000275 AC XY: 10AN XY: 363572
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2018 | Variant summary: MECP2 c.735C>G alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: five predict the variant strengthens a cryptic 5 prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 178616 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.00087 in the gnomAD database. This frequency within Latino control individuals is approximately 104-fold above the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.735C>G in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 31, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2018 | - - |
MECP2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2022 | 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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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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