NM_001110792.2:c.261G>A

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 c.225G>A (p.Pro75=) variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The c.225G>A (p.Pro75=) variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). In summary, the c.225G>A (p.Pro75=) variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170275/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000016 ( 0 hom. 3 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:5

Conservation

PhyloP100: -2.38

Publications

0 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.261G>A	p.Pro87Pro	synonymous_variant	Exon 2 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.225G>A	p.Pro75Pro	synonymous_variant	Exon 3 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.261G>A	p.Pro87Pro	synonymous_variant	Exon 2 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.225G>A	p.Pro75Pro	synonymous_variant	Exon 3 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

113248

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:

0.0000562

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

182956

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1097886

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35185

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54117

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40485

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

841925

Other (OTH)

AF:

0.00

AC:

AN:

46084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000265

AC:

AN:

113248

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

35386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31271

American (AMR)

AF:

0.00

AC:

AN:

10822

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3603

South Asian (SAS)

AF:

0.00

AC:

AN:

2811

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000562

AC:

AN:

53346

Other (OTH)

AF:

0.00

AC:

AN:

1529

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

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:

0.0000269

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 03, 2007

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Dec 28, 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. -

Rett syndrome

Benign:2

Mar 15, 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). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

Oct 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.225G>A (p.Pro75=) variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The c.225G>A (p.Pro75=) variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). In summary, the c.225G>A (p.Pro75=) variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.26

(source)

DANN

Benign

0.65

PhyloP100

-2.4

PromoterAI

-0.33

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over