X-154030655-AGGTGGAGGTGGGGGCAGGGGT-AGGT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1PM4BP6BS2

The NM_001110792.2(MECP2):c.1191_1208delCCTGCCCCCACCTCCACC(p.Leu398_Pro403del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000254 in 748,978 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P397P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 0 hem., cov: 0)

Exomes 𝑓: 0.000025 ( 0 hom. 5 hem. )

Failed GnomAD Quality Control

Consequence

MECP2
NM_001110792.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2O:1

Conservation

PhyloP100: 5.01

Publications

2 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: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 22 benign, 17 uncertain in NM_001110792.2

PM4

Nonframeshift variant in NON repetitive region in NM_001110792.2.

BP6

Variant X-154030655-AGGTGGAGGTGGGGGCAGG-A is Benign according to our data. Variant chrX-154030655-AGGTGGAGGTGGGGGCAGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 143358.

BS2

High AC in GnomAdExome4 at 19 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1191_1208delCCTGCCCCCACCTCCACC	p.Leu398_Pro403del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.1155_1172delCCTGCCCCCACCTCCACC	p.Leu386_Pro391del	disruptive_inframe_deletion	Exon 4 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.1191_1208delCCTGCCCCCACCTCCACC	p.Leu398_Pro403del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.1155_1172delCCTGCCCCCACCTCCACC	p.Leu386_Pro391del	disruptive_inframe_deletion	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.0000439

AC:

AN:

45532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000909

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:

0.0000401

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000600

AC:

AN:

166750

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:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000254

AC:

AN:

748978

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

224762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18512

American (AMR)

AF:

0.00

AC:

AN:

27695

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10881

East Asian (EAS)

AF:

0.00

AC:

AN:

12706

South Asian (SAS)

AF:

0.0000261

AC:

AN:

38313

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16777

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2319

European-Non Finnish (NFE)

AF:

0.0000303

AC:

AN:

594302

Other (OTH)

AF:

0.00

AC:

AN:

27473

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.607

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000439

AC:

AN:

45532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

10470

show subpopulations

African (AFR)

AF:

0.0000909

AC:

AN:

11002

American (AMR)

AF:

0.00

AC:

AN:

3587

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1283

East Asian (EAS)

AF:

0.00

AC:

AN:

1630

South Asian (SAS)

AF:

0.00

AC:

AN:

802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000401

AC:

AN:

24924

Other (OTH)

AF:

0.00

AC:

AN:

583

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Other:1

Feb 18, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of 6 amino acids in a non-repeat region; In silico analysis indicates that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18810657)

RettBASE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Dec 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Rett syndrome

Benign:1

May 03, 2024

Centre for Population Genomics, CPG

Significance:Likely 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 likely benign. At least the following criteria are met: This variant is present in 21 indivisuals in gnomAD v4 including 5 hemizygotes. The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.0

Mutation Taster

=62/138

disease causing (long InDel)

(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