rs267608332
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2
The NM_001110792.2(MECP2):c.1196_1202del(p.Pro399LeufsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 552,051 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P399P) has been classified as Benign.
Frequency
Consequence
NM_001110792.2 frameshift
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.1196_1202del | p.Pro399LeufsTer20 | frameshift_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.1160_1166del | p.Pro387LeufsTer20 | frameshift_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000303391.11 | c.1160_1166del | p.Pro387LeufsTer20 | frameshift_variant | 4/4 | 1 | NM_004992.4 | P1 | |
MECP2 | ENST00000453960.7 | c.1196_1202del | p.Pro399LeufsTer20 | frameshift_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000407218.5 | c.*532_*538del | 3_prime_UTR_variant | 4/4 | 5 | ||||
MECP2 | ENST00000628176.2 | c.*532_*538del | 3_prime_UTR_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000609 AC: 1AN: 16414Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 4652
GnomAD3 exomes AF: 0.00000755 AC: 1AN: 132529Hom.: 0 AF XY: 0.0000204 AC XY: 1AN XY: 49033
GnomAD4 exome AF: 0.0000392 AC: 21AN: 535637Hom.: 0 AF XY: 0.0000255 AC XY: 4AN XY: 156659
GnomAD4 genome AF: 0.0000609 AC: 1AN: 16414Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 4652
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:3
Pathogenic, 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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from the NHLBI exome sequencing project (PM2_Supporting). It has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease (PS4_Moderate, RettBase internal database, PMID: 20031356, PMID: 21160487, PMID: 15389714). - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Nov 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | The frameshift c.1196_1202del(p.Pro399LeufsTer20) variant in MECP2 gene has been reported previously in individual(s) affected with Rett syndrome (Hadzsiev K, et. al., 2011; Kárteszi J, et. al., 2004). The p.Pro399LeufsTer20 variant has been reported with allele frequency of 0.0008% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Proline 399, changes this amino acid to Leucine residue, and creates a premature Stop codon at position 20 of the new reading frame, denoted p.Pro399LeufsTer20. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2016 | The c.1160_1166delCCCCACC pathogenic variant in the MECP2 gene has been reported previously in association with Rett syndrome (Hadzsiev et al., 2011; Karteszi et al., 2004; Monnerat et al., 2010). The deletion causes a frameshift starting with codon Proline 387, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 20 of the new reading frame, denoted p.P387LfsX20. The c.1160_1166delCCCCACC variant is predicted to cause loss of normal protein function through protein truncation, as the last 100 amino acids are replaced with 19 incorrect ones. Additionally, this variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at