chrX-154031076-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP6_Moderate

The NM_001110792.2(MECP2):​c.788C>T​(p.Pro263Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,067 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P263R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

7
8
2

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 6.17

Publications

3 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: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 8 uncertain in NM_001110792.2
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant X-154031076-G-A is Benign according to our data. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MECP2NM_001110792.2 linkc.788C>T p.Pro263Leu missense_variant Exon 3 of 3 ENST00000453960.7 NP_001104262.1 P51608-2A0A140VKC4Q59FJ6
MECP2NM_004992.4 linkc.752C>T p.Pro251Leu missense_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.788C>T p.Pro263Leu missense_variant Exon 3 of 3 1 NM_001110792.2 ENSP00000395535.2 P51608-2
MECP2ENST00000303391.11 linkc.752C>T p.Pro251Leu missense_variant Exon 4 of 4 1 NM_004992.4 ENSP00000301948.6 P51608-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1098067
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
363437
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26398
American (AMR)
AF:
0.00
AC:
0
AN:
35200
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19383
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54143
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40519
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4137
European-Non Finnish (NFE)
AF:
0.00000119
AC:
1
AN:
841994
Other (OTH)
AF:
0.00
AC:
0
AN:
46093
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
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:
0.0000457
Hom.:
0

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Feb 15, 2002
RettBASE
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:curation

- -

Rett syndrome Benign:1
Mar 20, 2024
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 3.0, this variant is classified as likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). PMID 10944854 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.;T;T
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Uncertain
0.63
D;D;D;D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Benign
1.9
L;.;.;.
PhyloP100
6.2
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.9
D;D;.;.
REVEL
Uncertain
0.51
Sift
Uncertain
0.0030
D;D;.;.
Sift4G
Uncertain
0.0040
D;D;.;D
Polyphen
0.99
D;D;.;.
Vest4
0.49
MutPred
0.13
Loss of glycosylation at P251 (P = 0.0209);.;Loss of glycosylation at P251 (P = 0.0209);.;
MVP
0.97
ClinPred
0.98
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.55
gMVP
0.88
Mutation Taster
=84/16
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs61750229; hg19: chrX-153296527; API