NM_001110792.2:c.1169C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -2 ACMG points: 2P and 4B. BS2PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Ala378Gly variant has been observed in 3 individuals with Rett syndrome (PMID 16473305, 20031356, 11960578) (PS4_moderate). The p.Ala378Gly variant is observed in at least 7 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Ala378Gly variant in MECP2 is present in 3 female and 1 male individual(s) in gnomAD (0.002%) (not sufficient to meet BS1 criteria). In summary, the p.Ala378Gly variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PS4_moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270202/MONDO:0010726/036

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:6B:3

Conservation

PhyloP100: 2.85

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: Uncertain_significance. The variant received -2 ACMG points.

PS4

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.1169C>G	p.Ala390Gly	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1133C>G	p.Ala378Gly	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.1169C>G	p.Ala390Gly	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.1133C>G	p.Ala378Gly	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

109524

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000333

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000966

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:

0.0000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000172

AC:

AN:

174908

AF XY:

0.0000159

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000737

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000697

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000640

AC:

AN:

1093136

Hom.:

Cov.:

AF XY:

0.00000834

AC XY:

AN XY:

359746

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26266

American (AMR)

AF:

0.0000571

AC:

AN:

35043

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19296

East Asian (EAS)

AF:

0.00

AC:

AN:

30157

South Asian (SAS)

AF:

0.00

AC:

AN:

53895

European-Finnish (FIN)

AF:

0.0000257

AC:

AN:

38887

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3764

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

839963

Other (OTH)

AF:

0.0000218

AC:

AN:

45865

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000274

AC:

AN:

109568

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31848

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

30069

American (AMR)

AF:

0.0000964

AC:

AN:

10369

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2610

East Asian (EAS)

AF:

0.00

AC:

AN:

3471

South Asian (SAS)

AF:

0.00

AC:

AN:

2509

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

52262

Other (OTH)

AF:

0.00

AC:

AN:

1494

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

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:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Uncertain:3Benign:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2010

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

- -

Jan 10, 2024

Centre for Population Genomics, CPG

Significance:Uncertain significance

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 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). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). (PMID: 16473305, 20031356, 11960578) -

Oct 30, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The p.Ala378Gly variant in MECP2 (NM_004992.4) is observed in at least 7 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Ala378Gly variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The highest population minor allele frequency of the p.Ala378Gly variant in MECP2 in gnomAD v4.1 is 0.00006606 in Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Ala378Gly variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). -

not provided

Uncertain:1Benign:1

Aug 12, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16473305, 11960578, 26984561) -

Inborn genetic diseases

Uncertain:1

Sep 22, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1133C>G (p.A378G) 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 1133, causing the alanine (A) at amino acid position 378 to be replaced by a glycine (G). This variant has been detected individuals with classic Rett syndrome and Rett syndrome-like features (Milunsky, 2001; Philippe, 2006; Monnerat, 2010; Zahorakova, 2016). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MECP2-related disorder

Uncertain:1

Jun 29, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MECP2 c.1133C>G variant is predicted to result in the amino acid substitution p.Ala378Gly. This variant was reported in three individuals with Rett syndrome or Rett-like features (Milunsky et al. 2001. PubMed ID: 11960578; Philippe et al. 2006. PubMed ID: 16473305; Zahorakova et al. 2016. PubMed ID: 26984561). However, this variant is also reported in 0.0072% of alleles in individuals of Latino descent in gnomAD, including four heterozygotes and one hemizygote (http://gnomad.broadinstitute.org/variant/X-153296146-G-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

Benign

0.088

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.25

T;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.26

T;T

MetaSVM

Uncertain

-0.089

MutationAssessor

Benign

0.0

N;.

PhyloP100

2.9

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.68

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.17

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.63

P;P

Vest4

0.33

MVP

0.97

ClinPred

0.082

GERP RS

5.0

Varity_R

0.14

gMVP

0.32

Mutation Taster

=99/1

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