X-154030591-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_SupportingBP5

This summary comes from the ClinGen Evidence Repository: The p.Cys413Arg variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_Supporting). The p.Cys413Arg variant in MECP2 (NM_004992.3) is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary the p.Cys413Arg variant in MECP2 (NM_004992.3) is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM2_Supporting, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA208666/MONDO:0010726/032

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:1

Conservation

PhyloP100: 2.50

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP5

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.1273T>C	p.Cys425Arg	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1237T>C	p.Cys413Arg	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.1273T>C	p.Cys425Arg	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.1237T>C	p.Cys413Arg	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000183

AC:

AN:

1095672

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26381

American (AMR)

AF:

0.00

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19359

East Asian (EAS)

AF:

0.00

AC:

AN:

30180

South Asian (SAS)

AF:

0.00

AC:

AN:

54133

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4082

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841775

Other (OTH)

AF:

0.0000217

AC:

AN:

46046

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jul 17, 2015

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. -

Jan 20, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rett syndrome

Uncertain:1

May 05, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The p.Cys413Arg variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_Supporting). The p.Cys413Arg variant in MECP2 (NM_004992.3) is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary the p.Cys413Arg variant in MECP2 (NM_004992.3) is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM2_Supporting, BP5). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.29

T;.

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.69

N;.

PhyloP100

2.5

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.45

N;N

REVEL

Uncertain

0.42

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.38

T;T

Polyphen

0.0

B;B

Vest4

0.15

MutPred

0.20

Gain of MoRF binding (P = 0.017);.;

MVP

1.0

ClinPred

0.24

GERP RS

4.3

Varity_R

0.83

gMVP

0.21

Mutation Taster

=86/14

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over