X-154032183-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.377+24C>A variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.377+24C>A variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199494/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000012 ( 0 hom. 3 hem. )

Consequence

MECP2
NM_001110792.2 intron

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:3O:1

Conservation

PhyloP100: 1.42

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: Likely_benign. The variant received -5 ACMG points.

BP4

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

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.413+24C>A		intron_variant	Intron 2 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.377+24C>A		intron_variant	Intron 3 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.413+24C>A		intron_variant	Intron 2 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.377+24C>A		intron_variant	Intron 3 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

112978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000932

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

182455

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1046142

Hom.:

Cov.:

AF XY:

0.00000933

AC XY:

AN XY:

321534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25383

American (AMR)

AF:

0.000114

AC:

AN:

35148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19056

East Asian (EAS)

AF:

0.00

AC:

AN:

30003

South Asian (SAS)

AF:

0.00

AC:

AN:

52913

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40437

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3976

European-Non Finnish (NFE)

AF:

0.0000101

AC:

AN:

794849

Other (OTH)

AF:

0.0000225

AC:

AN:

44377

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.00000885

AC:

AN:

112978

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31151

American (AMR)

AF:

0.0000932

AC:

AN:

10733

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3609

South Asian (SAS)

AF:

0.00

AC:

AN:

2778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6263

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53339

Other (OTH)

AF:

0.00

AC:

AN:

1521

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Oct 12, 2023

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 2.0, this variant is classified as likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in ExAC is between 0.008% and 0.03% (BS1). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

Oct 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the c.377+24C>A variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.377+24C>A variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4). -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Uncertain:1

Mar 10, 2010

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jul 30, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Other:1

RettBASE

Significance:not provided

Review Status:flagged submission

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.1

(source)

DANN

Benign

0.77

PhyloP100

1.4

PromoterAI

-0.062

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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