rs1557137821
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001110792.2(MECP2):c.286C>T(p.Arg96Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,097,327 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 24)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )
Consequence
MECP2
NM_001110792.2 missense
NM_001110792.2 missense
Scores
12
3
2
Clinical Significance
Conservation
PhyloP100: 6.03
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.759
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.286C>T | p.Arg96Trp | missense_variant | 2/3 | ENST00000453960.7 | NP_001104262.1 | |
MECP2 | NM_004992.4 | c.250C>T | p.Arg84Trp | missense_variant | 3/4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.286C>T | p.Arg96Trp | missense_variant | 2/3 | 1 | NM_001110792.2 | ENSP00000395535 | ||
MECP2 | ENST00000303391.11 | c.250C>T | p.Arg84Trp | missense_variant | 3/4 | 1 | NM_004992.4 | ENSP00000301948 | P1 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD3 genomes
Cov.:
24
GnomAD4 exome AF: 0.00000182 AC: 2AN: 1097327Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 362753
GnomAD4 exome
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2
AN:
1097327
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31
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0
AN XY:
362753
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GnomAD4 genome Cov.: 24
GnomAD4 genome
Cov.:
24
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe neonatal-onset encephalopathy with microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 27, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 84 of the MECP2 protein (p.Arg84Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 536586). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12843318, 21831886) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;T;T;T;T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;.;.;.
Sift4G
Uncertain
D;D;D;D;.;D;D
Polyphen
D;D;.;.;.;.;.
Vest4
MutPred
Gain of ubiquitination at K82 (P = 0.0222);.;Gain of ubiquitination at K82 (P = 0.0222);.;Gain of ubiquitination at K82 (P = 0.0222);.;.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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