chrX-154032530-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1BP4BP7

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.54C>G p.Leu18= variant in MECP2 (NM_004992.1) is 0.042% in the African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Leu18= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.54C>G p.Leu18= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA243345/MONDO:0010726/032

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 1 hem., cov: 24)
Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

2

Clinical Significance

Benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 0.568

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 -10 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BP7
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MECP2NM_001110792.2 linkc.90C>G p.Leu30Leu synonymous_variant Exon 2 of 3 ENST00000453960.7 NP_001104262.1 P51608-2A0A140VKC4Q59FJ6
MECP2NM_004992.4 linkc.54C>G p.Leu18Leu synonymous_variant Exon 3 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.90C>G p.Leu30Leu synonymous_variant Exon 2 of 3 1 NM_001110792.2 ENSP00000395535.2 P51608-2
MECP2ENST00000303391.11 linkc.54C>G p.Leu18Leu synonymous_variant Exon 3 of 4 1 NM_004992.4 ENSP00000301948.6 P51608-1

Frequencies

GnomAD3 genomes
AF:
0.0000622
AC:
7
AN:
112613
Hom.:
0
Cov.:
24
show subpopulations
Gnomad AFR
AF:
0.000226
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000336
AC:
6
AN:
178410
AF XY:
0.0000152
show subpopulations
Gnomad AFR exome
AF:
0.000460
Gnomad AMR exome
AF:
0.00
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:
0.00000366
AC:
4
AN:
1094125
Hom.:
0
Cov.:
31
AF XY:
0.00000277
AC XY:
1
AN XY:
361283
show subpopulations
African (AFR)
AF:
0.000152
AC:
4
AN:
26392
American (AMR)
AF:
0.00
AC:
0
AN:
35203
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:
54139
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
36836
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4127
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
841779
Other (OTH)
AF:
0.00
AC:
0
AN:
46057
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
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
AF:
0.0000621
AC:
7
AN:
112667
Hom.:
0
Cov.:
24
AF XY:
0.0000287
AC XY:
1
AN XY:
34811
show subpopulations
African (AFR)
AF:
0.000226
AC:
7
AN:
31027
American (AMR)
AF:
0.00
AC:
0
AN:
10726
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2653
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3611
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2764
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6184
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
216
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
53281
Other (OTH)
AF:
0.00
AC:
0
AN:
1526
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000793

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Jun 23, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 27, 2015
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Rett syndrome Benign:1
Jun 15, 2023
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
Significance:Benign
Review Status:reviewed by expert panel
Collection Method:curation

The allele frequency of the c.54C>G p.Leu18= variant in MECP2 (NM_004992.1) is 0.042% in the African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Leu18= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.54C>G p.Leu18= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1
Apr 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

MECP2-related disorder Benign:1
Aug 24, 2023
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_noAF
Benign
-0.54
CADD
Benign
7.6
DANN
Benign
0.79
PhyloP100
0.57
PromoterAI
-0.0091
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=100/0
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: rs372500343; hg19: chrX-153297981; API