rs61753965
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001110792.2(MECP2):c.1252C>T(p.Gln418Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000914 in 1,094,534 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q418Q) has been classified as Likely benign.
Frequency
Consequence
NM_001110792.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.1252C>T | p.Gln418Ter | stop_gained | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.1216C>T | p.Gln406Ter | stop_gained | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.1252C>T | p.Gln418Ter | stop_gained | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.1216C>T | p.Gln406Ter | stop_gained | 4/4 | 1 | NM_004992.4 | P1 | |
MECP2 | ENST00000407218.5 | c.*588C>T | 3_prime_UTR_variant | 4/4 | 5 | ||||
MECP2 | ENST00000628176.2 | c.*588C>T | 3_prime_UTR_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 21
GnomAD4 exome AF: 9.14e-7 AC: 1AN: 1094534Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 361380
GnomAD4 genome ? Cov.: 21
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Jan 18, 2018 | - - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Sep 27, 2012 | - - |
Pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Mar 13, 2024 | 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 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 10986043, 22476991, 14560307, ClinVar Variation ID: 143441) This variant is absent from gnomAD (PM2_Supporting). - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Gln437Alafs*49) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 143441). This premature translational stop signal has been observed in individuals with MECP2-related conditions (PMID: 10986043, 14560307, 22476991). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln406*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acid(s) of the MECP2 protein. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2022 | Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29655203, 14560307, 22476991, 23452848, 10986043) - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | curation | RettBASE | Sep 27, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at