rs61753975

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.1366G>A(p.Ala456Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,209,785 control chromosomes in the GnomAD database, including 1 homozygotes. There are 324 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A456V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., 17 hem., cov: 22)

Exomes 𝑓: 0.00085 ( 1 hom. 307 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.556

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014973402).

BP6

Variant X-154030498-C-T is Benign according to our data. Variant chrX-154030498-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000771 (86/111598) while in subpopulation NFE AF = 0.00117 (62/53021). AF 95% confidence interval is 0.000936. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 86 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1366G>A	p.Ala456Thr	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1330G>A	p.Ala444Thr	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.1366G>A	p.Ala456Thr	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.1330G>A	p.Ala444Thr	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

AN:

111547

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000474

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000828

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00117

Gnomad OTH

AF:

0.000666

GnomAD2 exomes

AF:

0.000949

AC:

174

AN:

183388

AF XY:

0.000958

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.000729

Gnomad ASJ exome

AF:

0.00134

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.000751

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.000883

GnomAD4 exome

AF:

0.000849

AC:

932

AN:

1098187

Hom.:

Cov.:

AF XY:

0.000844

AC XY:

307

AN XY:

363557

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

26399

American (AMR)

AF:

0.000738

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

19385

East Asian (EAS)

AF:

0.000232

AC:

AN:

30205

South Asian (SAS)

AF:

0.000351

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.000815

AC:

AN:

40489

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.000939

AC:

791

AN:

842125

Other (OTH)

AF:

0.000564

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000771

AC:

AN:

111598

Hom.:

Cov.:

AF XY:

0.000503

AC XY:

AN XY:

33780

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

30739

American (AMR)

AF:

0.000568

AC:

AN:

10572

Ashkenazi Jewish (ASJ)

AF:

0.000378

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2616

European-Finnish (FIN)

AF:

0.000828

AC:

AN:

6041

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00117

AC:

AN:

53021

Other (OTH)

AF:

0.000657

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.00108

Hom.:

Bravo

AF:

0.000790

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00104

AC:

ExAC

AF:

0.000988

AC:

120

EpiCase

AF:

0.00142

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Dec 16, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 2010

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 03, 2013

GeneDx

Significance: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. -

Mar 27, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MECP2 c.1330G>A (p.Ala444Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00098 in 200146 control chromosomes in the gnomAD database, including 55 hemizygotes. The observed variant frequency is approximately 118.11 fold above the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating the impact on protein function of c.1330G>A have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Sep 26, 2024

Athena Diagnostics

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

- -

Rett syndrome

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: 11738860, PMID: 11055898). This variant did not segregate in a similarly affected family member (BS4_Supporting, PMID: 11738860) -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 23, 2025

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

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.24

T;.

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-0.34

N;.

PhyloP100

0.56

PrimateAI

Benign

0.41

PROVEAN

Benign

0.040

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.79

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0050

B;B

Vest4

0.098

MVP

0.94

ClinPred

0.0026

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.042

gMVP

0.39

Mutation Taster

=95/5

polymorphism (auto)

(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