X-154030648-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_001110792.2(MECP2):c.1216G>C(p.Glu406Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E406K) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 16)

Exomes 𝑓: 0.0000025 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.61

Publications

11 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.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 23 benign, 18 uncertain in NM_001110792.2

BP4

Computational evidence support a benign effect (MetaRNN=0.08193946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1216G>C	p.Glu406Gln	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.1180G>C	p.Glu394Gln	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.1216G>C	p.Glu406Gln	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.1180G>C	p.Glu394Gln	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

72329

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000249

AC:

AN:

803373

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

243967

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19305

American (AMR)

AF:

0.00

AC:

AN:

29311

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11851

East Asian (EAS)

AF:

0.00

AC:

AN:

13488

South Asian (SAS)

AF:

0.00

AC:

AN:

43259

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18663

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2571

European-Non Finnish (NFE)

AF:

0.00000315

AC:

AN:

634885

Other (OTH)

AF:

0.00

AC:

AN:

30040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

72335

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

16031

African (AFR)

AF:

0.00

AC:

AN:

17935

American (AMR)

AF:

0.00

AC:

AN:

5615

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1974

East Asian (EAS)

AF:

0.00

AC:

AN:

2189

South Asian (SAS)

AF:

0.00

AC:

AN:

1142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

129

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

39648

Other (OTH)

AF:

0.00

AC:

AN:

911

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.32

T;.

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.082

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.34

N;.

PhyloP100

1.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.50

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.54

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0

B;B

Vest4

0.082

MutPred

0.14

Loss of glycosylation at P393 (P = 0.0613);.;

MVP

0.83

ClinPred

0.073

GERP RS

2.9

Varity_R

0.078

gMVP

0.21

Mutation Taster

=92/8

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

Computational scores

Splicing

Publications

Other links and lift over