chrX-154097618-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001110792.2(MECP2):c.48C>T(p.Gly16Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000108 in 924,253 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001110792.2 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.48C>T | p.Gly16Gly | synonymous_variant | Exon 1 of 3 | ENST00000453960.7 | NP_001104262.1 | |
MECP2 | NM_004992.4 | c.-113C>T | 5_prime_UTR_variant | Exon 1 of 4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.48C>T | p.Gly16Gly | synonymous_variant | Exon 1 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
MECP2 | ENST00000303391.11 | c.-113C>T | 5_prime_UTR_variant | Exon 1 of 4 | 1 | NM_004992.4 | ENSP00000301948.6 |
Frequencies
GnomAD3 genomes Cov.: 20
GnomAD4 exome AF: 0.00000108 AC: 1AN: 924253Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 284217
GnomAD4 genome Cov.: 20
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:3
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 pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in an individual with Rett syndrome with confirmed parental relationships (PS2, PMID: 23866855). Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3, PMID: 23866855). At least one patient with this variant has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PP4, PMID: 23866855). This variant is absent from gnomAD (PM2_Supporting). -
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not provided Pathogenic:2
The c.48 C>T variant in the MECP2 gene was reported previously as an assumed de novo variant in a female with classic Rett syndrome and has also been detected as a confirmed de novo variant in a patient tested at GeneDx (Sheikh et al., 2013). The c.48 C>T variant is a silent substitution that alters a conserved position in the MECP2_e1 transcript. In silico models predict it creates a cryptic splice donor site, leading to abnormal gene splicing. Sequencing of cDNA from lymphocytes of a patient heterozygous for c.48 C>T confirmed this variant results in alternative splicing that introduces a premature stop codon, and quantitative mRNA analysis detected both the mutant transcript and reduced levels of the wildtype MECP2_e1 transcript compared to healthy controls (Sheikh et al., 2013). The c.48 C>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.48 C>T as a pathogenic variant. -
The MECP2 c.48C>T; p.Gly16= variant (rs786205045, ClinVar Variation ID: 189773), is reported in the literature in an individual with classic Rett syndrome (Sheikh 2013). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Splicing studies found this variant results in premature splicing of exon 1 creating a frameshift event resulting in a premature stop codon (Sheikh 2013). Based on available information, this variant is considered to be pathogenic. REFERENCES Sheikh TI et al. A synonymous change, p.Gly16Gly in MECP2 Exon 1, causes a cryptic splice event in a Rett syndrome patient. Orphanet J Rare Dis. 2013 Jul 19;8:108. PMID: 23866855. -
Inborn genetic diseases Pathogenic:1
The c.48C>T (p.G16G) alteration is located in exon 1 (coding exon 1) of the MECP2 gene. This alteration consists of a C to T substitution at nucleotide position 48. This nucleotide substitution does not change the amino acid at codon 16. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one female with features consistent with Rett syndrome (Sheikh, 2013). This nucleotide position is highly conserved in available vertebrate species. Functional analysis demonstrated that this alteration causes abnormal splicing (Sheikh, 2013). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at