rs61753971

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Gly428Ser (NM_004992) variant in MECP2 is 0.014% in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly428Ser variant is observed in at least 2 unaffected individuals (PMID:11238684, PMID:12161600) (BS2). In summary the p.Gly428Ser variant in MECP2 is classified as Benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA121707/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000061 ( 0 hom. 23 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1B:7

Conservation

PhyloP100: 2.49

Publications

9 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: Benign. The variant received -8 ACMG points.

BS1

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.1318G>A	p.Gly440Ser	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.1282G>A	p.Gly428Ser	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.1318G>A	p.Gly440Ser	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.1282G>A	p.Gly428Ser	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.0000993

AC:

AN:

110805

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000658

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000957

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000131

AC:

AN:

182729

AF XY:

0.000134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.0000642

Gnomad NFE exome

AF:

0.000122

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000610

AC:

AN:

1097691

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363127

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26397

American (AMR)

AF:

0.000227

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.000111

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.0000998

AC:

AN:

40095

Middle Eastern (MID)

AF:

0.000968

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000534

AC:

AN:

842028

Other (OTH)

AF:

0.00

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.0000993

AC:

AN:

110805

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

33021

show subpopulations

African (AFR)

AF:

0.0000658

AC:

AN:

30416

American (AMR)

AF:

0.0000957

AC:

AN:

10453

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3529

South Asian (SAS)

AF:

0.00

AC:

AN:

2587

European-Finnish (FIN)

AF:

0.000167

AC:

AN:

5989

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

52791

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000132

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly

Pathogenic:1Benign:1

Aug 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rett syndrome

Benign:2

Aug 14, 2023

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 2.0, 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 higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2, PMID: 11238684). -

May 10, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the p.Gly428Ser (NM_004992) variant in MECP2 is 0.014% in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly428Ser variant is observed in at least 2 unaffected individuals (PMID: 11238684, PMID: 12161600) (BS2). In summary the p.Gly428Ser variant in MECP2 is classified as Benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2). -

not specified

Benign:1

Oct 04, 2002

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Inborn genetic diseases

Benign:1

Sep 12, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Jun 09, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28454995, 11238684, 12161600, 11896461, 30560934) -

MECP2-related disorder

Benign:1

Oct 26, 2022

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

0.090

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.26

T;.

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

-0.093

MutationAssessor

Benign

0.46

N;.

PhyloP100

2.5

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.020

N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.44

T;T

Polyphen

0.96

D;D

Vest4

0.13

MVP

1.0

ClinPred

0.057

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.20

gMVP

0.14

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