X-154030661-AGGTGGGG-AG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP2BA1

This summary comes from the ClinGen Evidence Repository: The p.Pro390_Pro391del variant in MECP2 (NM_004992.3) has been reported in an individual with intellectual disability (PMID 21982064). The allele frequency of the p.Pro390_Pro391del variant in MECP2 is 0.1158% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Pro390_Pro391del variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID:23696494) (BP2). In summary, the p.Pro390_Pro391del variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA232911/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000061 ( 0 hom., 0 hem., cov: 0)

Exomes 𝑓: 0.000069 ( 0 hom. 15 hem. )

Consequence

MECP2
NM_001110792.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:4O:1

Conservation

PhyloP100: 3.20

Publications

0 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 -9 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MECP2	NM_001110792.2	MANE Select	c.1197_1202delCCCACC	p.Pro400_Pro401del	disruptive_inframe_deletion	Exon 3 of 3	NP_001104262.1
MECP2	NM_004992.4	MANE Plus Clinical	c.1161_1166delCCCACC	p.Pro388_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	NP_004983.1
MECP2	NM_001316337.2		c.882_887delCCCACC	p.Pro295_Pro296del	disruptive_inframe_deletion	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1197_1202delCCCACC	p.Pro400_Pro401del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000395535.2
MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1161_1166delCCCACC	p.Pro388_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000301948.6
MECP2	ENST00000630151.3	TSL:5	c.1161_1166delCCCACC	p.Pro388_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes

AF:

0.0000609

AC:

AN:

16414

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00267

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000121

AC:

AN:

132529

AF XY:

0.000143

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000691

AC:

AN:

535637

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

156659

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13489

American (AMR)

AF:

0.00

AC:

AN:

17484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7694

East Asian (EAS)

AF:

0.000255

AC:

AN:

7836

South Asian (SAS)

AF:

0.00126

AC:

AN:

22278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13189

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1775

European-Non Finnish (NFE)

AF:

0.0000115

AC:

AN:

432938

Other (OTH)

AF:

0.000106

AC:

AN:

18954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.616

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:

0.0000609

AC:

AN:

16414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

4652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

3899

American (AMR)

AF:

0.00

AC:

AN:

1398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

448

East Asian (EAS)

AF:

0.00

AC:

AN:

763

South Asian (SAS)

AF:

0.00267

AC:

AN:

374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

509

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

8681

Other (OTH)

AF:

0.00

AC:

AN:

209

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Oct 11, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The p.Pro390_Pro391del variant in MECP2 (NM_004992.3) has been reported in an individual with intellectual disability (PMID 21982064). The allele frequency of the p.Pro390_Pro391del variant in MECP2 is 0.1158% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Pro390_Pro391del variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID: 23696494) (BP2). In summary, the p.Pro390_Pro391del variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP2).

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). Variant found in a case with an alternate molecular basis for disease (BP5_supporting, PMID: 23696494).

not provided

Benign:1Other:1

Dec 21, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27929079, 11055898, 21982064)

RettBASE

Significance:not provided

Review Status:flagged submission

Collection Method:literature only

Angelman syndrome

Uncertain:1

Aug 10, 2012

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Oct 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=151/49

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over