X-154097642-CGCGGCGGCG-CGCG

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.18_23delCGCCGC(p.Ala7_Ala8del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000381 in 1,024,509 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.000036 ( 0 hom. 4 hem. )

Consequence

MECP2
NM_001110792.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel U:2B:4

Conservation

PhyloP100: 4.00

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-CGCGGCG-C is Benign according to our data. Variant chrX-154097642-CGCGGCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 156657.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 6 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.18_23delCGCCGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.-143_-138delCGCCGC		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_23delCGCCGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.-143_-138delCGCCGC		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000563

AC:

AN:

106552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000101

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000197

Gnomad OTH

AF:

0.000695

GnomAD2 exomes

AF:

0.00

AC:

AN:

59976

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000360

AC:

AN:

917924

Hom.:

AF XY:

0.0000140

AC XY:

AN XY:

284702

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000202

AC:

AN:

19832

American (AMR)

AF:

0.0000585

AC:

AN:

17095

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13264

East Asian (EAS)

AF:

0.00

AC:

AN:

22366

South Asian (SAS)

AF:

0.0000315

AC:

AN:

31738

European-Finnish (FIN)

AF:

0.0000463

AC:

AN:

21607

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3231

European-Non Finnish (NFE)

AF:

0.0000332

AC:

AN:

751915

Other (OTH)

AF:

0.0000271

AC:

AN:

36876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000345798), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.0000563

AC:

AN:

106585

Hom.:

Cov.:

AF XY:

0.0000992

AC XY:

AN XY:

30233

show subpopulations

African (AFR)

AF:

0.000101

AC:

AN:

29735

American (AMR)

AF:

0.00

AC:

AN:

10354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2596

East Asian (EAS)

AF:

0.000308

AC:

AN:

3243

South Asian (SAS)

AF:

0.00

AC:

AN:

2490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5017

Middle Eastern (MID)

AF:

0.00

AC:

AN:

209

European-Non Finnish (NFE)

AF:

0.0000197

AC:

AN:

50872

Other (OTH)

AF:

0.000686

AC:

AN:

1457

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000340

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Apr 18, 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.-143_-138del variant in MECP2 (NM_004992.4) in gnomAD v4.0 is 0.0001412 in the African/African 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). Larger deletions encompassing this region (c.-143_-138del) have been observed in an unaffected mother and father (Invitae internal database) (BP3). This variant has been observed in an individual with neurodevelopment disorder (PMID 1717659) (not sufficient for PS4_supporting). In summary, the c.-143_-138del variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP3). -

Jan 16, 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 between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

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

- -

MECP2-related disorder

Uncertain:1

Mar 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MECP2 c.18_23del6 variant is predicted to result in an in-frame deletion (p.Ala7_Ala8del). This variant has been reported in an individual with intellectual disability (Harvey et al. 2007. PubMed ID: 17171659). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Oct 27, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.0

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