X-154030648-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP5BS2BA1BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Glu394Lys variant in MECP2 is 0.035% in East 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.Glu394Lys variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Glu394Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Glu394Lys variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Glu394Lys variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170197/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000083 ( 0 hom., 1 hem., cov: 16)

Exomes 𝑓: 0.00011 ( 0 hom. 27 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 1.61

Publications

11 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 -14 ACMG points.

BP4

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

BP5

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

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.1216G>A	p.Glu406Lys	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.1180G>A	p.Glu394Lys	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.1216G>A	p.Glu406Lys	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.1180G>A	p.Glu394Lys	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.0000829

AC:

AN:

72333

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000558

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000455

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000101

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000874

AC:

AN:

171619

AF XY:

0.0000801

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000749

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000297

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000778

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000110

AC:

AN:

803418

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

243984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19306

American (AMR)

AF:

0.000102

AC:

AN:

29311

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11852

East Asian (EAS)

AF:

0.00126

AC:

AN:

13492

South Asian (SAS)

AF:

0.000116

AC:

AN:

43263

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18666

Middle Eastern (MID)

AF:

0.000389

AC:

AN:

2572

European-Non Finnish (NFE)

AF:

0.0000866

AC:

AN:

634914

Other (OTH)

AF:

0.000233

AC:

AN:

30042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.0000829

AC:

AN:

72333

Hom.:

Cov.:

AF XY:

0.0000624

AC XY:

AN XY:

16021

show subpopulations

African (AFR)

AF:

0.0000558

AC:

AN:

17925

American (AMR)

AF:

0.00

AC:

AN:

5609

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1974

East Asian (EAS)

AF:

0.000455

AC:

AN:

2197

South Asian (SAS)

AF:

0.00

AC:

AN:

1144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

144

European-Non Finnish (NFE)

AF:

0.000101

AC:

AN:

39647

Other (OTH)

AF:

0.00

AC:

AN:

901

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

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:

0.00

Hom.:

ESP6500AA

AF:

0.000263

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 05, 2014

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Aug 23, 2016

GeneDx

Significance:Likely 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. -

Oct 12, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The MECP2 c.1180G>A (p.Glu394Lys) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (Mutation Taster not captured here due to low p-value) predict a benign outcome for this variant. This variant was found in 13/184110 (5 hemizygotes) control chromosomes (gnomAD) at a frequency of 0.0000706, which is approximately 8 times the estimated maximal expected allele frequency of a pathogenic MECP2 variant (0.0000083), suggesting this variant is likely a benign polymorphism. A publication reported a RETT syndrome patient who carried another pathogenic MECP2 variant p.Arg168X and the patient's unaffected father also carried the variant of interest (Chapleau_2013), strongly supporting benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

Rett syndrome

Benign:3

Jul 09, 2015

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: Variant is present at ≥0.0003 (0.03%) in any sub-population (East Asian) (BA1). -

Mar 26, 2021

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.Glu394Lys variant in MECP2 is 0.035% in East 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.Glu394Lys variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Glu394Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Glu394Lys variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Glu394Lys variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MECP2-related disorder

Benign:1

Aug 18, 2022

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

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

T;.

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.90

L;.

PhyloP100

1.6

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.79

N;N

REVEL

Uncertain

0.47

Sift

Benign

0.046

D;D

Sift4G

Benign

0.83

T;T

Polyphen

0.0

B;B

Vest4

0.18

MVP

0.89

ClinPred

0.017

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.075

gMVP

0.21

Mutation Taster

=93/7

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over