rs201314910
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.Ala378Val (NM_004992) variant in MECP2 is 0.014% in East Asian sub population in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala378Val variant is observed in at least 2 unaffected individuals (PMID 15737703)(BS2). In summary, the p.Ala378Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170175/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.1169C>T | p.Ala390Val | missense_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.1133C>T | p.Ala378Val | missense_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.1169C>T | p.Ala390Val | missense_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.1133C>T | p.Ala378Val | missense_variant | 4/4 | 1 | NM_004992.4 | P1 | |
MECP2 | ENST00000407218.5 | c.*505C>T | 3_prime_UTR_variant | 4/4 | 5 | ||||
MECP2 | ENST00000628176.2 | c.*505C>T | 3_prime_UTR_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000100 AC: 11AN: 109524Hom.: 0 Cov.: 22 AF XY: 0.0000315 AC XY: 1AN XY: 31794
GnomAD3 exomes AF: 0.0000515 AC: 9AN: 174908Hom.: 0 AF XY: 0.0000319 AC XY: 2AN XY: 62720
GnomAD4 exome AF: 0.000129 AC: 141AN: 1093137Hom.: 0 Cov.: 35 AF XY: 0.000103 AC XY: 37AN XY: 359747
GnomAD4 genome ? AF: 0.000100 AC: 11AN: 109524Hom.: 0 Cov.: 22 AF XY: 0.0000315 AC XY: 1AN XY: 31794
ClinVar
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | curation | RettBASE | Mar 10, 2010 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 31, 2019 | Variant summary: MECP2 c.1133C>T (p.Ala378Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 175188 control chromosomes (2 hemizygotes). The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. c.1133C>T has been reported in the literature in one female individual affected with Rett Syndrome and patient's unaffected father (Fukuda_2005). This report suggests the variant does not associate with Rett Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 29, 2014 | - - |
not provided Pathogenic:1Benign:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2021 | This variant is associated with the following publications: (PMID: 15737703) - |
Rett syndrome Benign:2
Benign, 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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). - |
Benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | May 10, 2022 | The allele frequency of the p.Ala378Val (NM_004992) variant in MECP2 is 0.014% in East Asian sub population in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala378Val variant is observed in at least 2 unaffected individuals (PMID 15737703)(BS2). In summary, the p.Ala378Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | - - |
MECP2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 11, 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