X-154097642-CGCGGCGGCG-CGCGGCGGCGGCGGCGGCG

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.15_23dupCGCCGCCGC(p.Ala6_Ala8dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000381 in 1,024,889 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000037 ( 0 hom. 11 hem. )

Consequence

MECP2
NM_001110792.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel U:2B:3

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-CGCGGCGGCG is Benign according to our data. Variant chrX-154097642-C-CGCGGCGGCG is described in ClinVar as Likely_benign. ClinVar VariationId is 189762.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 5 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.15_23dupCGCCGCCGC	p.Ala6_Ala8dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.-146_-138dupCGCCGCCGC		5_prime_UTR_variant	Exon 1 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.15_23dupCGCCGCCGC	p.Ala6_Ala8dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.-146_-138dupCGCCGCCGC		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.0000469

AC:

AN:

106553

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000193

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:

0.0000590

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000500

AC:

AN:

59976

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

918336

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

284950

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19840

American (AMR)

AF:

0.000175

AC:

AN:

17113

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13271

East Asian (EAS)

AF:

0.0000447

AC:

AN:

22386

South Asian (SAS)

AF:

0.000157

AC:

AN:

31784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3234

European-Non Finnish (NFE)

AF:

0.0000332

AC:

AN:

752182

Other (OTH)

AF:

0.00

AC:

AN:

36892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

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:

0.0000469

AC:

AN:

106553

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

30189

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29680

American (AMR)

AF:

0.000193

AC:

AN:

10343

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2596

East Asian (EAS)

AF:

0.00

AC:

AN:

3256

South Asian (SAS)

AF:

0.00

AC:

AN:

2499

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5017

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.0000590

AC:

AN:

50882

Other (OTH)

AF:

0.00

AC:

AN:

1438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

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). -

Jun 25, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The highest population minor allele frequency of the c.-146_-138dup variant in MECP2 (NM_004992.4), also known as c.15_23dup (p.Ala6_Ala8dup) in transcript NM_001110792.2, in gnomAD v4.1 is 0.00018 in the Admixed American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The c.-146_-138dup variant is observed in at least 1 unaffected individual (Internal database - Ambry) (BS2_Supporting). In summary, the c.-146_-138dup variant in MECP2 (NM_004992.4) is classified as likely benign based on the ACMG/AMP criteria (BS1, BS2_Supporting). -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MECP2 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001110792.1, and corresponds to NM_004992.3:c.-146_-138dup in the primary transcript. This variant, c.15_23dup, results in the insertion of 3 amino acid(s) of the MECP2 protein (p.Ala6_Ala8dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398123566, gnomAD 0.007%). This variant has been observed in individual(s) with intellectual disability (PMID: 17171659). This variant is also known as ins[GCC]3, (Ala)7>(Ala)10. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Uncertain:1

Nov 01, 2007

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

- -

Inborn genetic diseases

Benign:1

Apr 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over