X-154030639-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Glu397Lys variant in MECP2 (NM_004992) is 0.393% in European (Non-Finnish) 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.Glu397Lys variant is observed in at least 2 unaffected individuals (PMID 10577905,12384770, RettBASE) (BS2). In summary, the p.Glu397Lys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211306/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., 44 hem., cov: 18)

Exomes 𝑓: 0.0049 ( 11 hom. 1499 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:20

Conservation

PhyloP100: 0.579

Publications

18 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 -12 ACMG points.

BS2

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

BA1

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.1225G>A	p.Glu409Lys	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.1189G>A	p.Glu397Lys	missense_variant	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.1225G>A	p.Glu409Lys	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.1189G>A	p.Glu397Lys	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

258

AN:

82421

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00176

Gnomad AMR

AF:

0.00195

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000678

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00472

Gnomad OTH

AF:

0.00289

GnomAD2 exomes

AF:

0.00223

AC:

388

AN:

173875

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.00119

Gnomad AMR exome

AF:

0.000809

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000731

Gnomad FIN exome

AF:

0.00140

Gnomad NFE exome

AF:

0.00394

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00485

AC:

4761

AN:

981331

Hom.:

Cov.:

AF XY:

0.00481

AC XY:

1499

AN XY:

311627

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

23364

American (AMR)

AF:

0.000822

AC:

AN:

32842

Ashkenazi Jewish (ASJ)

AF:

0.0000639

AC:

AN:

15646

East Asian (EAS)

AF:

0.0000846

AC:

AN:

23628

South Asian (SAS)

AF:

0.000779

AC:

AN:

48781

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

26401

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

3217

European-Non Finnish (NFE)

AF:

0.00574

AC:

4409

AN:

768697

Other (OTH)

AF:

0.00446

AC:

173

AN:

38755

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

178

356

533

711

889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.00313

AC:

258

AN:

82427

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

AN XY:

19179

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

20710

American (AMR)

AF:

0.00195

AC:

AN:

6675

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2252

East Asian (EAS)

AF:

0.00

AC:

AN:

2562

South Asian (SAS)

AF:

0.000681

AC:

AN:

1468

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

3145

Middle Eastern (MID)

AF:

0.00

AC:

AN:

169

European-Non Finnish (NFE)

AF:

0.00472

AC:

207

AN:

43827

Other (OTH)

AF:

0.00286

AC:

AN:

1050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00229

Hom.:

Bravo

AF:

0.00288

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00242

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00359

AC:

ExAC

AF:

0.00251

AC:

304

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:10

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 03, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2013

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Jul 15, 2016

GeneDx

Significance: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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 19, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu397Lys variant in MECP2 is classified as a benign, because It has been has been identified in 0.39% (328/84800) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP), including 131 hemizygous individuals. While it has been reported in individuals with Rett syndrome and has also been reported in ClinVar (Variant ID 95187). However, in one family a second causative variant was identified in a female proband with Rett, while her her unaffected sister and their hemizygous father also carried the p.Glu397Lys variant (Wan 1999). Computational prediction tools and conservation analysis suggest that the p.Glu397Lys variant may not impact the protein. ACMG/AMP Criteria applied: BS1; BP4_Strong; BP2. -

Jun 22, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rett syndrome

Uncertain:1Benign:3

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). -

May 10, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the p.Glu397Lys variant in MECP2 (NM_004992) is 0.393% in European (Non-Finnish) 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.Glu397Lys variant is observed in at least 2 unaffected individuals (PMID 10577905,12384770, RettBASE) (BS2). In summary, the p.Glu397Lys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). -

Sep 04, 2013

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 26, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

History of neurodevelopmental disorder

Benign:1

Aug 01, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.23

T;.

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.81

N;.

PhyloP100

0.58

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.020

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.44

T;T

Sift4G

Benign

0.99

T;T

Polyphen

0.0

B;B

Vest4

0.32

MVP

0.74

ClinPred

0.0080

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.24

Mutation Taster

=92/8

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over