X-154032268-G-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001110792.2(MECP2):c.352C>G(p.Arg118Gly) variant causes a missense change. 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. R118Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 25)
Consequence
MECP2
NM_001110792.2 missense
NM_001110792.2 missense
Scores
11
5
1
Clinical Significance
Conservation
PhyloP100: 4.35
Genes affected
MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001110792.2
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-154032267-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
?
Variant X-154032268-G-C is Pathogenic according to our data. Variant chrX-154032268-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.352C>G | p.Arg118Gly | missense_variant | 2/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.316C>G | p.Arg106Gly | missense_variant | 3/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.352C>G | p.Arg118Gly | missense_variant | 2/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.316C>G | p.Arg106Gly | missense_variant | 3/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 25
GnomAD3 genomes
?
Cov.:
25
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 25
GnomAD4 genome
?
Cov.:
25
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Jan 21, 2008 | - - |
Likely 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 likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). (PMID: 16473305, 16183801) Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). - |
MECP2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 25, 2023 | The MECP2 c.316C>G variant is predicted to result in the amino acid substitution p.Arg106Gly. This variant has been reported in at least 4 affected individuals with a Rett syndrome phenotype. However, at least one unaffected female was identified to be heterozygous for the variant (Proband ID 2195; http://mecp2.chw.edu.au/mecp2/mecp2_variant_page.php?&id=2194; http://mecp2.chw.edu.au/mecp2/mecp2_variant_page.php?&id=2194; Philippe et al. 2006. PubMed ID: 16473305; Bienvenu et al. 2002. PubMed ID: 12180070). X chromosome inactivation is thought to contribute to phenotypic variability in females (Knudsen et al. 2006. PubMed ID: 16823396; Fang et al. 2022. PubMed ID: 35318820). Furthermore, several other missense variants impacting the same amino acid residue (p.Arg106Trp, p.Arg106Gln, p.Arg106Leu) have been reported in individuals with Rett syndrome phenotypes (http://mecp2.chw.edu.au/mecp2/mecp2_upgrade_proband_list_copy.php). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Take together, this variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;T;D;D;T;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;.;.;.
Sift4G
Uncertain
D;T;D;D;.;D;D
Polyphen
D;D;.;.;.;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0263);.;Loss of MoRF binding (P = 0.0263);.;Loss of MoRF binding (P = 0.0263);.;.;
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at