rs185957513

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110792.2(MECP2):c.1409G>A(p.Arg470His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,209,420 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 88 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R470C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 8 hem., cov: 22)

Exomes 𝑓: 0.00019 ( 0 hom. 80 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.70

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056291252).

BP6

Variant X-154030455-C-T is Benign according to our data. Variant chrX-154030455-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000194 (213/1098179) while in subpopulation EAS AF = 0.000894 (27/30206). AF 95% confidence interval is 0.00063. There are 0 homozygotes in GnomAdExome4. There are 80 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 18 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1409G>A	p.Arg470His	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.1373G>A	p.Arg458His	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.1409G>A	p.Arg470His	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.1373G>A	p.Arg458His	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

111191

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000566

Gnomad SAS

AF:

0.000779

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000229

AC:

AN:

183515

AF XY:

0.000294

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000732

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

213

AN:

1098179

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

AN XY:

363533

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26402

American (AMR)

AF:

0.000284

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19385

East Asian (EAS)

AF:

0.000894

AC:

AN:

30206

South Asian (SAS)

AF:

0.000222

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000175

AC:

147

AN:

842073

Other (OTH)

AF:

0.000239

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000162

AC:

AN:

111241

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

33433

show subpopulations

African (AFR)

AF:

0.000131

AC:

AN:

30619

American (AMR)

AF:

0.00

AC:

AN:

10536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.000568

AC:

AN:

3524

South Asian (SAS)

AF:

0.000781

AC:

AN:

2561

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000189

AC:

AN:

52940

Other (OTH)

AF:

0.00

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000704

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 28, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2009

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

not provided

Benign:2

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18810657, 28394482) -

Rett syndrome

Benign:1

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 18810657, PMID: 18810657). Variant found in a case with an alternate molecular basis for disease (BP5_Supporting, PMID: 18810657). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Aug 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MECP2 NM_004992.3 exon 4 p.Arg458His (c.1373G>A): This variant has been reported in the literature in 1 male individual with features of Rett syndrome, but did not meet diagnostic criteria (reported as p.Arg470His, Zhang 2017 PMID:28394482). This variant is present in 0.01% (10/52947) of European alleles, including 5 hemizygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/X-154030455-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign (Variation ID:95193). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

MECP2-related disorder

Benign:1

Jun 03, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

0.24

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.056

T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

0.90

L;.

PhyloP100

2.7

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.93

N;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;D

Vest4

0.19

MVP

0.98

ClinPred

0.032

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.15

Mutation Taster

=94/6

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