rs193922678

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP5BS2

This summary comes from the ClinGen Evidence Repository: The p.Val481Met variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Val481Met variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.007% in the Latino/Admixed American sub population including 2 hemizygous males (not sufficient for BS1). The p.Val481Met variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Val481Met variant has been observed in 1 individual with a Rett like disorder (PMID 22277191) and 1 individual with nonspecific neurological phenotypes (PMID 29655203) (Not sufficient for PS4_supporting). In summary, the p.Val481Met variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA208886/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000031 ( 0 hom. 15 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:5

Conservation

PhyloP100: 6.15

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: Likely_benign. The variant received -5 ACMG points.

BP5

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

BS2

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.1477G>A	p.Val493Met	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1441G>A	p.Val481Met	missense_variant	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.1477G>A	p.Val493Met	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.1441G>A	p.Val481Met	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

183492

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1098211

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363565

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.0000852

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000332

AC:

AN:

842115

Other (OTH)

AF:

0.0000434

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.0000269

AC:

AN:

111518

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33670

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30634

American (AMR)

AF:

0.00

AC:

AN:

10595

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00

AC:

AN:

2584

European-Finnish (FIN)

AF:

0.000166

AC:

AN:

6039

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

53024

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Uncertain:2Benign:2

Sep 27, 2012

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

- -

Feb 18, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The p.Val481Met variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Val481Met variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.007% in the Latino/Admixed American sub population including 2 hemizygous males (not sufficient for BS1). The p.Val481Met variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Val481Met variant has been observed in 1 individual with a Rett like disorder (PMID 22277191) and 1 individual with nonspecific neurological phenotypes (PMID 29655203) (Not sufficient for PS4_supporting). In summary, the p.Val481Met variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). -

Mar 13, 2015

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The Val493Met variant has not been identified in 87757 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). The Valine at position 493 is highly conserved in evolution, though computational tools do not provide strong support for or against an impact to the protein. The variant has been reported previously in two female patients with Rett syndrome (Fong et al 2009/MECP2 database and Zvereff et al 2012), however family history was not provided. This variant is more likely pathogenic but additional studies are needed to fully assess its clinical significance. -

Mar 14, 2024

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 3.0, this variant is classified as likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Variant is found in an individual with an alternate molecular basis of disease (BP5). -

not provided

Uncertain:1Benign:1

Aug 24, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a variant of uncertain significance in a female with history of developmental regression and meeting clinical criteria for Rett syndrome (Zvereff et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29655203, 22277191) -

Jun 15, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Feb 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MECP2-related disorder

Benign:1

Mar 12, 2024

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

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.36

T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

1.0

L;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.62

N;N

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

0.90

P;P

Vest4

0.45

MutPred

0.14

Loss of sheet (P = 0.1158);.;

MVP

1.0

ClinPred

0.36

GERP RS

4.9

Varity_R

0.63

gMVP

0.33

Mutation Taster

=25/75

disease causing

(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