X-154097642-CGCGGCGGCG-CGCGGCGGCGGCGGCG

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001110792.2(MECP2):c.18_23dupCGCCGC(p.Ala7_Ala8dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000341 in 1,024,887 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 85 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 5 hem., cov: 21)

Exomes 𝑓: 0.00034 ( 0 hom. 80 hem. )

Consequence

MECP2
NM_001110792.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:3B:10

Conservation

PhyloP100: 3.94

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant X-154097642-C-CGCGGCG is Benign according to our data. Variant chrX-154097642-C-CGCGGCG is described in ClinVar as [Benign]. Clinvar id is 189763.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.18_23dupCGCCGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.-143_-138dupCGCCGC		5_prime_UTR_variant	Exon 1 of 4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.18_23dupCGCCGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.-143_-138dupCGCCGC		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000347

AC:

AN:

106552

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

AN XY:

30188

show subpopulations

Gnomad AFR

AF:

0.000168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000967

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000400

Gnomad FIN

AF:

0.000199

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000550

Gnomad OTH

AF:

0.000695

GnomAD3 exomes

AF:

0.000167

AC:

AN:

59976

Hom.:

AF XY:

0.00

AC XY:

AN XY:

15452

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.000113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000231

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000234

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000340

AC:

312

AN:

918302

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

AN XY:

284924

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000117

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000268

Gnomad4 SAS exome

AF:

0.000252

Gnomad4 FIN exome

AF:

0.000139

Gnomad4 NFE exome

AF:

0.000362

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.000347

AC:

AN:

106585

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

AN XY:

30233

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0000966

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000402

Gnomad4 FIN

AF:

0.000199

Gnomad4 NFE

AF:

0.000550

Gnomad4 OTH

AF:

0.000686

Bravo

AF:

0.000363

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Uncertain:1Benign:2

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2024

Centre for Population Genomics, CPG

Significance: 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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

Dec 08, 2022

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.-143_-138dup variant in MECP2 (NM_004992.3) is 0.033% in 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 c.-143_-138dup variant is observed in at least 2 unaffected individuals (PMID: 15367913, internal database) (BS2). The c.-143_-138dup variant has been observed in at least 2 individuals with neurological disorders (PMID: 33880059, 16829352) (PS4 not met). In summary, the c.-143_-138dup variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1Benign:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

Jul 17, 2013

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23_24insCGCCGC (aka c.18_23dupCGCCGC) variant results in the duplication of two amino acid residues in a poorly conserved region of the MECP2_e1 transcript. This variant has been reported as a benign polymorphism because it was identified in a female with Rett syndrome and her unaffected mother in one family and did not cosegregate with intellectual disability in another family (Evans et al., 2005; Quenard et al., 2006). However, in another study variations in the number of Alanine or Glycine repeats in this region of the protein were found in approximately 1% of females with intellectual disability but a significantly smaller percentage of controls, so the authors suggested these variants may be associated with an increased risk for intellectual disability (Harvey et al., 2007). Internal exome population data indicates this variant has been seen in 2 unaffected males. The variant is found in CHILD-EPI panel(s). -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MECP2: BS2 -

not specified

Benign:2

Jun 12, 2013

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jun 16, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MECP2 c.-143_-138dupCGCCGC (also known as c.18_23dup6 and c.16_21dup) is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00035 in 105710 control chromosomes, including 5 hemizygotes (gnomAD v3.1.2). The observed variant frequency is approximately 42-fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. c.-143_-138dupCGCCGC has been reported in the literature in individuals affected with Rett Syndrome and intellectual disability (examples: Guo_2021, Zahorakova_2016 and Quenard_2006). In these reports, authors have classified the variant as non pathogenic or variant of uncertain significance. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=1) and as benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

Inborn genetic diseases

Benign:1

Dec 01, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 20, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MECP2 NM_001110792.1 p.Ala7_Ala8dup (c.18_23dup): This variant has been reported in the literature in 2 individuals with Rett syndrome; however, this variant was also present in the unaffected mothers of these individuals. For one case, this variant did not segregate with disease in 1 affected sister (though the sibling's phenotype was reported to be more mild) (Evans 2005 PMID:15367913, Quenard 2006 PMID:16829352). In both published reports, the authors commented that X-inactivation was not skewed and suggested that this variant may not cause disease, but the impact of this variant remained uncertain. This variant is present in 0.05% (28/50882) of European alleles including 2 hemizygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/X-154097642-C-CGCGGCG?dataset=gnomad_r3). This variant is present in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/189763/). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame duplication of 2 Alanine residues at position 7 (within a string of Alanine repeats) and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Autism, susceptibility to, X-linked 3

Benign:1

Sep 25, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. This variant was detected in hemizygous state. -

MECP2-related disorder

Benign:1

Jan 19, 2021

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over