X-154030747-G-C

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 allele frequency of p.Pro361Ala variant in MECP2 (NM_004992) gene in the European (non-Finnish) subpopulation in gnomAD is 0.005% which does not satisfy any of the population frequency criteria for this disorder. The p.Pro361Ala variant is observed as 3 hemizygotes in 6 occurrences in gnomAD (BS2). The p.Pro361Ala variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Pro361Ala variant does not occur in either well-characterized functional domain of the MECP2. The in silico evidence is inconclusive for the variant. In summary, the p.Pro361Ala variant in MECP2 is classified as Likely Benign based on ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170169/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000091 ( 0 hom. 36 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:4

Conservation

PhyloP100: 1.48

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: 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.1117C>G	p.Pro373Ala	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1081C>G	p.Pro361Ala	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.1117C>G	p.Pro373Ala	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.1081C>G	p.Pro361Ala	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000379

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000277

AC:

AN:

180727

AF XY:

0.0000301

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:

0.0000497

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000911

AC:

100

AN:

1097522

Hom.:

Cov.:

AF XY:

0.0000992

AC XY:

AN XY:

362982

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26377

American (AMR)

AF:

0.00

AC:

AN:

35164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19347

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54107

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40443

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

841745

Other (OTH)

AF:

0.000109

AC:

AN:

46049

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000180

AC:

AN:

110886

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30431

American (AMR)

AF:

0.00

AC:

AN:

10517

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3531

South Asian (SAS)

AF:

0.00

AC:

AN:

2620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5981

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000379

AC:

AN:

52759

Other (OTH)

AF:

0.00

AC:

AN:

1483

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Jun 25, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The highest population minor allele frequency of the p.Pro361Ala variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.0001029 in the Non-Finnish European population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Pro361Ala variant is observed in at least 2 unaffected individuals (Internal database - Ambry Genetics) (BS2). The p.Pro361Ala variant is found in a patient with an alternate molecular basis of disease (internal database - Labcorp Genetics) (BP5). In summary, the p.Pro361Ala variant in MECP2 (NM_004992.4) is classified as benign based on ACMG/AMP criteria (BS1, BS2, BP5). (MECP2 Specifications v.4.1; curation approved on 06/25/2025) -

Jan 10, 2024

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 3.0, 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 between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

not specified

Uncertain:1

Feb 03, 2006

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

- -

Inborn genetic diseases

Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1081C>G (p.P361A) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to G substitution at nucleotide position 1081, causing the proline (P) at amino acid position 361 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Mar 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MECP2-related disorder

Benign:1

Apr 09, 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

Benign

0.054

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.23

T;.

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.4

L;.

PhyloP100

1.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.080

N;N

REVEL

Uncertain

0.37

Sift

Benign

0.039

D;T

Sift4G

Benign

0.10

T;T

Polyphen

0.088

B;B

Vest4

0.13

MVP

0.87

ClinPred

0.034

GERP RS

4.2

Varity_R

0.056

gMVP

0.66

Mutation Taster

=95/5

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over