chrX-154031255-G-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2BP4BP6_Very_StrongBP7

The NM_001110792.2(MECP2):​c.609C>T​(p.Pro203Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,240 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P203P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

1
4
7

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.20

Publications

0 publications found
Variant links:
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]
MECP2 Gene-Disease associations (from GenCC):
  • chromosome Xq28 duplication syndrome
    Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
  • Rett syndrome
    Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
  • severe neonatal-onset encephalopathy with microcephaly
    Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • syndromic X-linked intellectual disability Lubs type
    Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
  • atypical Rett syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • non-syndromic X-linked intellectual disability
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • X-linked intellectual disability-psychosis-macroorchidism syndrome
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • systemic lupus erythematosus
    Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31350952).
BP6
Variant X-154031255-G-A is Benign according to our data. Variant chrX-154031255-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 143625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=1.2 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MECP2NM_001110792.2 linkc.609C>T p.Pro203Pro synonymous_variant Exon 3 of 3 ENST00000453960.7 NP_001104262.1 P51608-2A0A140VKC4Q59FJ6
MECP2NM_004992.4 linkc.573C>T p.Pro191Pro synonymous_variant Exon 4 of 4 ENST00000303391.11 NP_004983.1 P51608-1D3YJ43Q59FJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MECP2ENST00000453960.7 linkc.609C>T p.Pro203Pro synonymous_variant Exon 3 of 3 1 NM_001110792.2 ENSP00000395535.2 P51608-2
MECP2ENST00000303391.11 linkc.573C>T p.Pro191Pro synonymous_variant Exon 4 of 4 1 NM_004992.4 ENSP00000301948.6 P51608-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD2 exomes
AF:
0.00000545
AC:
1
AN:
183328
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1098240
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
363600
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26403
American (AMR)
AF:
0.0000284
AC:
1
AN:
35206
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19386
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30206
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54148
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40529
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4137
European-Non Finnish (NFE)
AF:
0.00000119
AC:
1
AN:
842127
Other (OTH)
AF:
0.00
AC:
0
AN:
46098
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
23
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Dec 03, 2007
RettBASE
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:curation

- -

Rett syndrome Benign:1
Aug 14, 2023
Centre for Population Genomics, CPG
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation

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 likely 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). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1
May 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

MECP2-related disorder Benign:1
May 08, 2024
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
9.2
DANN
Benign
0.96
DEOGEN2
Benign
0.095
T;T
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.60
T;T
M_CAP
Pathogenic
0.62
D
MetaRNN
Benign
0.31
T;T
MetaSVM
Uncertain
0.77
D
PhyloP100
1.2
REVEL
Uncertain
0.54
Sift4G
Uncertain
0.018
D;D
Vest4
0.35
MutPred
0.52
Loss of loop (P = 9e-04);.;
MVP
0.98
ClinPred
0.16
T
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=75/25
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs61749710; hg19: chrX-153296706; COSMIC: COSV100318484; COSMIC: COSV100318484; API