rs61750239

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received -4 ACMG points: 1P and 5B. PP3BS2BP5

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the p.Arg268Trp variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00002175 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Arg268Trp variant is observed in at least 2 unaffected individuals (PMID 12750821, LabCorp Genetics (formerly Invitae) and GeneDx internal databases) (BS2). The p.Arg268Trp variant is found in a patient with an alternate molecular basis of disease (PMID:32340510) (BP5). The p.Arg268Trp variant in MECP2 has been reported in male individuals described to have x-linked intellectual disability (PMID:12750821), in female individuals described to have Rett syndrome (PMID:18842453), and in unaffected female and male individuals (PMID:1275082, GeneDx internal data) (PP4_not met). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg268Trp variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2, BP5, PP3). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) LINK:https://erepo.genome.network/evrepo/ui/classification/CA233007/MONDO:0010726/036

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. 3 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:8B:2O:1

Conservation

PhyloP100: 5.13

Publications

2 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: Uncertain_significance. The variant received -4 ACMG points.

PP3

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.838C>T	p.Arg280Trp	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.802C>T	p.Arg268Trp	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.838C>T	p.Arg280Trp	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.802C>T	p.Arg268Trp	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000355

AC:

AN:

112533

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000930

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000548

AC:

AN:

182455

AF XY:

0.00

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1098176

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363548

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000285

AC:

AN:

842129

Other (OTH)

AF:

0.00

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.0000355

AC:

AN:

112533

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34697

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30970

American (AMR)

AF:

0.0000930

AC:

AN:

10753

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3569

South Asian (SAS)

AF:

0.00

AC:

AN:

2772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53201

Other (OTH)

AF:

0.00

AC:

AN:

1514

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

Alfa

AF:

0.0000310

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Benign:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1Other:1

RettBASE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 25, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as pathogenic [in ClinVar/in a well-curated database/through personal communication] but additional evidence is not available [ref]; Reported as pathogenic [in ClinVar/in a well-curated database/through personal communication] but additional evidence is not available [ref]; This variant is associated with the following publications: (PMID: 11469283, 18842453, 12750821) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rett syndrome

Uncertain:2

May 07, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The highest population minor allele frequency of the p.Arg268Trp variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00002175 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Arg268Trp variant is observed in at least 2 unaffected individuals (PMID 12750821, LabCorp Genetics (formerly Invitae) and GeneDx internal databases) (BS2). The p.Arg268Trp variant is found in a patient with an alternate molecular basis of disease (PMID: 32340510) (BP5). The p.Arg268Trp variant in MECP2 has been reported in male individuals described to have x-linked intellectual disability (PMID: 12750821), in female individuals described to have Rett syndrome (PMID: 18842453), and in unaffected female and male individuals (PMID: 1275082, GeneDx internal data) (PP4_not met). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg268Trp variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2, BP5, PP3). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) -

Jan 03, 2025

Centre for Population Genomics, CPG

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

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 a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2) (PMID: 12750821) (ClinGen expert panel: https://erepo.genome.network/evrepo/ui/classification/CA233007/MONDO:0010726/016).Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3).At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4) (PMID: 18842453) -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Sep 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 268 of the MECP2 protein (p.Arg268Trp). This variant is present in population databases (rs61750239, gnomAD 0.002%). This missense change has been observed in individual(s) with X-linked intellectual disability and/or Rett syndrome (PMID: 11469283, 12750821, 18842453). ClinVar contains an entry for this variant (Variation ID: 143700). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Unlikely to be causative of Rett syndrome (XLD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MECP2-related disorder

Uncertain:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MECP2 c.802C>T variant is predicted to result in the amino acid substitution p.Arg268Trp. This variant was reported in an individual with Rett syndrome; however, the individual also harbored a nonsense variant two amino acids downstream, with both changes reported as de novo (p.[Arg268Trp(;) Arg270*]; Erlandson et al 2001. PubMed ID: 11469283; http://mecp2.chw.edu.au/). Two additional papers document this variant in at least three individuals with Rett Syndrome or X-linked intellectual disability 13, yet these patients are not characterized (Renieri et al. 2003. PubMed ID: 12750821; Buoni et al. 2008. PubMed ID: 18842453). This variant is reported in 0.0022% of alleles in individuals of European (non-Finnish) descent in gnomAD V2 and has been reported in 4 hemizygotes in updated gnomAD V4 data (https://gnomad.broadinstitute.org/variant/X-154031026-G-A?dataset=gnomad_r4). To our knowledge, no functional studies have been done to support this variant's pathogenicity. Other labs report this missense change as either a variant of uncertain significance or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/143700/). X-inactivation skewing may alter disease severity in females with pathogenic MECP2 alterations. At this time, the clinical significance of this variant is uncertain due to insufficient functional and genetic evidence. -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Benign:1

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.3

M;.;.

PhyloP100

5.1

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.2

D;D;.

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.034

D;T;D

Polyphen

1.0

D;D;.

Vest4

0.66

MVP

1.0

ClinPred

0.92

GERP RS

4.7

Varity_R

0.62

gMVP

0.90

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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