rs61749737
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP6_Strong
The NM_001110792.2(MECP2):c.715C>G(p.Gln239Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q239H) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )
Failed GnomAD Quality Control
Consequence
MECP2
NM_001110792.2 missense
NM_001110792.2 missense
Scores
2
6
9
Clinical Significance
Conservation
PhyloP100: 3.27
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 Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP6
?
Variant X-154031149-G-C is Benign according to our data. Variant chrX-154031149-G-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 143656.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.715C>G | p.Gln239Glu | missense_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.679C>G | p.Gln227Glu | missense_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.715C>G | p.Gln239Glu | missense_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.679C>G | p.Gln227Glu | missense_variant | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2AN: 1098238Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 1AN XY: 363592
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
2
AN:
1098238
Hom.:
Cov.:
36
AF XY:
AC XY:
1
AN XY:
363592
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3Benign:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Rett syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Mar 15, 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 a variant of uncertain significance. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Oct 11, 2022 | The p.Gln227Glu variant in MECP2 (NM_004992.3) has been reported in an individual with clinical features of MECP2-related conditions (PMID 17383248). The p.Gln227Glu variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Gln227Glu variant is observed in at least 1 unaffected male (internal database - Invitae) (BS2_supporting). In summary, the p.Gln227Glu variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Nov 01, 2007 | - - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;.
REVEL
Uncertain
Sift
Benign
T;T;.;.
Sift4G
Benign
T;T;.;T
Polyphen
B;B;.;.
Vest4
MutPred
Gain of ubiquitination at K223 (P = 0.0249);.;Gain of ubiquitination at K223 (P = 0.0249);.;
MVP
ClinPred
T
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