rs63390262
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2
This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro387Leu (NM_004992.3) variant in MECP2 is 0.026% in South Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro387Leu variant is observed in at least 2 unaffected individuals (PMID 12161600, GeneDx internal database) (BS2). In summary, the p.Pro387Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170185/MONDO:0010726/016
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.1196C>T | p.Pro399Leu | missense_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.1160C>T | p.Pro387Leu | missense_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.1196C>T | p.Pro399Leu | missense_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.1160C>T | p.Pro387Leu | missense_variant | 4/4 | 1 | NM_004992.4 | P1 | |
MECP2 | ENST00000407218.5 | c.*532C>T | 3_prime_UTR_variant | 4/4 | 5 | ||||
MECP2 | ENST00000628176.2 | c.*532C>T | 3_prime_UTR_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 9AN: 108861Hom.: 0 Cov.: 20 AF XY: 0.0000964 AC XY: 3AN XY: 31119 FAILED QC
GnomAD3 exomes AF: 0.0000752 AC: 13AN: 172961Hom.: 0 AF XY: 0.0000948 AC XY: 6AN XY: 63267
GnomAD4 exome AF: 0.0000671 AC: 73AN: 1088299Hom.: 0 Cov.: 36 AF XY: 0.0000870 AC XY: 31AN XY: 356327
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000826 AC: 9AN: 108906Hom.: 0 Cov.: 20 AF XY: 0.0000962 AC XY: 3AN XY: 31174
ClinVar
Submissions by phenotype
Rett syndrome Benign:2
Benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Dec 13, 2021 | The allele frequency of the p.Pro387Leu (NM_004992.3) variant in MECP2 is 0.026% in South Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro387Leu variant is observed in at least 2 unaffected individuals (PMID 12161600, GeneDx internal database) (BS2). In summary, the p.Pro387Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). - |
Benign, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Sep 25, 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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 08, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2021 | This variant is associated with the following publications: (PMID: 11309367, 16708070, 26755454, 28447035, 29206688) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2016 | The p.P387L variant (also known as c.1160C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 1160. The proline at codon 387 is replaced by leucine, an amino acid with similar properties. This variant was originally reported in a mentally retarded patient (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6). In addition, this variant was identified in homozygosity in a female with clinical suspicion of Rett syndrome; however, it was also found in her unaffected father (Bhanushali AA et al. J Clin Neurosci, 2016 Mar;25:127-9). This variant was previously reported in the SNPDatabase as rs63390262. In the NHLBI Exome Sequencing Project (ESP), this variant was not observed in 6325 samples with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Apr 10, 2002 | - - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 30, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 22, 2017 | Variant summary: The MECP2 c.1160C>T (p.Pro387Leu) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 17/186675 control chromosomes (gnomAD) at a frequency of 0.0000911, which is approximately 11 times the estimated maximal expected allele frequency of a pathogenic MECP2 variant (0.0000083), suggesting this variant is likely a benign polymorphism. The variant of interest has been reported via a publication in a homozygous female suspected to have Rett syndrome (Bhanushali_2016), however, her father also carried the variant and was stated to be mentally normal. In addition, one clinical diagnostic laboratory classified this variant as likely benign. Taken together, this variant is classified as likely benign. - |
Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 03, 2022 | - - |
MECP2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 08, 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at