rs61754459
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_001110792.2(MECP2):c.367A>G(p.Arg123Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R123K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.367A>G | p.Arg123Gly | missense_variant | 2/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.331A>G | p.Arg111Gly | missense_variant | 3/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.367A>G | p.Arg123Gly | missense_variant | 2/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.331A>G | p.Arg111Gly | missense_variant | 3/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 24
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Sep 05, 2002 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Mar 18, 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 likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID: 11241840 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). (PMID: 27929079, 11035019, 12843318, 21831886, 22923521, 31356990) Has been observed in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting). PMID: 18842453, 20728410, 11241840). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at