X-154097642-CGCGGCGGCG-CGCGGCGGCGGCG

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_001110792.2(MECP2):c.21_23dupCGC(p.Ala8dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0002 in 1,024,821 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 2 hem., cov: 21)

Exomes 𝑓: 0.00020 ( 0 hom. 34 hem. )

Consequence

MECP2
NM_001110792.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:6B:7

Conservation

PhyloP100: 3.94

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

MECP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001110792.2

BP6

Variant X-154097642-C-CGCG is Benign according to our data. Variant chrX-154097642-C-CGCG is described in ClinVar as Benign. ClinVar VariationId is 93556.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 17 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.21_23dupCGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.-140_-138dupCGC		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.21_23dupCGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.-140_-138dupCGC		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000160

AC:

AN:

106552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000337

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000307

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000199

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000275

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000333

AC:

AN:

59976

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000113

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:

0.000205

AC:

188

AN:

918269

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

284887

show subpopulations

African (AFR)

AF:

0.000202

AC:

AN:

19839

American (AMR)

AF:

0.00

AC:

AN:

17112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13271

East Asian (EAS)

AF:

0.000447

AC:

AN:

22384

South Asian (SAS)

AF:

0.0000944

AC:

AN:

31781

European-Finnish (FIN)

AF:

0.000139

AC:

AN:

21634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3234

European-Non Finnish (NFE)

AF:

0.000214

AC:

161

AN:

752123

Other (OTH)

AF:

0.000190

AC:

AN:

36891

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000160

AC:

AN:

106552

Hom.:

Cov.:

AF XY:

0.0000663

AC XY:

AN XY:

30188

show subpopulations

African (AFR)

AF:

0.0000337

AC:

AN:

29680

American (AMR)

AF:

0.00

AC:

AN:

10343

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2596

East Asian (EAS)

AF:

0.000307

AC:

AN:

3256

South Asian (SAS)

AF:

0.00

AC:

AN:

2499

European-Finnish (FIN)

AF:

0.000199

AC:

AN:

5017

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.000275

AC:

AN:

50881

Other (OTH)

AF:

0.00

AC:

AN:

1438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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.:

Bravo

AF:

0.000151

ClinVar

Significance: Benign

Submissions summary: Uncertain:6Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 23, 2013

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.23_24insCGC (aka c.21_23dupCGC) variant results in the duplication of a single Alanine residue in a poorly conserved region of the MECP2_e1 transcript. Although c.21_23dupCGC has not been published to our knowledge, it is reported in a gene specific mutation database as a variant of unknown pathogenicity. Additionally, a duplication of two Alanine residues in this region of the protein 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 co-segregate with intellectual disability in another family (Evans et al., 2005; Quenard et al., 2006). However, other 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). This variant has been observed to be inherited from an apparently unaffected mother. The variant is found in MECP2 panel(s). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 20, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MECP2: BS2 -

not specified

Uncertain:3

Dec 10, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MECP2 c.-140_-138dupCGC is located in the untranslated mRNA region upstream of the initiation codon in transcript NM_004992. The variant allele was found at a frequency of 3.3e-05 in 59976 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.-140_-138dupCGC in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as benign and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jun 01, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2006

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

- -

Rett syndrome

Benign:2

Feb 19, 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.-140_-138dup variant in MECP2 (NM_004992.3) is over 0.01% in South Asian, European (non-Finnish), and Latino/Admixed american sub populations in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The c.-140_-138dup variant in MECP2 is observed in at least 2 unaffected individuals (Invitae internal database) (BS2). The c.-140_-138dup variant is found in at least 3 patients with an alternate molecular basis of disease (Invitae internal database) (BP5). In summary the c.-140_-138dup variant in MECP2 is classified as a benign variant based on the ACMG/AMP criteria (BS1, BS2, BP5). -

Aug 14, 2023

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 2.0, 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 v3 is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 29, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

MECP2-related disorder

Benign:1

Dec 10, 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

PhyloP100

3.9

Mutation Taster

=71/29

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over