rs61753008

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PM1PM4BP6_Very_StrongBS2

The NM_001110792.2(MECP2):c.1204_1209delCCACCT(p.Pro402_Pro403del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000144 in 1,169,715 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P402P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 1 hem., cov: 0)

Exomes 𝑓: 0.00014 ( 0 hom. 48 hem. )

Consequence

MECP2
NM_001110792.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.01

Publications

4 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 -8 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 17 uncertain in NM_001110792.2

PM4

Nonframeshift variant in NON repetitive region in NM_001110792.2.

BP6

Variant X-154030654-CAGGTGG-C is Benign according to our data. Variant chrX-154030654-CAGGTGG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 12 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1204_1209delCCACCT	p.Pro402_Pro403del	conservative_inframe_deletion	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1168_1173delCCACCT	p.Pro390_Pro391del	conservative_inframe_deletion	Exon 4 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.1204_1209delCCACCT	p.Pro402_Pro403del	conservative_inframe_deletion	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.1168_1173delCCACCT	p.Pro390_Pro391del	conservative_inframe_deletion	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

90582

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000130

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000506

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000108

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000635

AC:

AN:

173240

AF XY:

0.0000788

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:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000145

AC:

156

AN:

1079130

Hom.:

AF XY:

0.000137

AC XY:

AN XY:

350942

show subpopulations

African (AFR)

AF:

0.0000765

AC:

AN:

26154

American (AMR)

AF:

0.00

AC:

AN:

34807

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19213

East Asian (EAS)

AF:

0.00

AC:

AN:

29894

South Asian (SAS)

AF:

0.0000566

AC:

AN:

52983

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3629

European-Non Finnish (NFE)

AF:

0.000174

AC:

145

AN:

831110

Other (OTH)

AF:

0.000132

AC:

AN:

45306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000132

AC:

AN:

90585

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

21323

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

22932

American (AMR)

AF:

0.000129

AC:

AN:

7725

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2368

East Asian (EAS)

AF:

0.00

AC:

AN:

3105

South Asian (SAS)

AF:

0.000510

AC:

AN:

1960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.000108

AC:

AN:

46497

Other (OTH)

AF:

0.00

AC:

AN:

1162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.000285

Hom.:

Bravo

AF:

0.000106

Asia WGS

AF:

0.000398

AC:

AN:

2521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2014

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Rett syndrome

Benign:2

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 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). -

Jul 07, 2015

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 22, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1168_1173delCCACCT variant in the MECP2 gene has been reported previously in girl with Rett syndrome (Djarmati et al., 2007). The deletion causes an in-frame loss of two Proline amino acids at codon 390 and 391, denoted p.Pro390_Pro391del. The c.1168_1173delCCACCT variant is described as a polymorphism in a gene specific mutation database as this variant was reported in an unaffected family member. Additionally, this variant is present in the NHLBI Exome Sequencing Project using alternate transcript numbering and has been observed in the homozygous state in a female and hemizygous in three males. This variant has been observed to be maternally inherited. The variant is found in MECP2 panel(s). -

MECP2-related disorder

Benign:1

Feb 17, 2023

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

5.0

Mutation Taster

=161/39

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