Genetic Variant MECP2:p.Gln140Glu (chrX-154031446-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_001110792.2(MECP2):c.418C>G(p.Gln140Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Q140K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.19

Publications

5 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001110792.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154031446-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 857143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MECP2	NM_001110792.2	MANE Select	c.418C>G	p.Gln140Glu	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
MECP2	NM_004992.4	MANE Plus Clinical	c.382C>G	p.Gln128Glu	missense	Exon 4 of 4	NP_004983.1	D3YJ43
MECP2	NM_001316337.2		c.103C>G	p.Gln35Glu	missense	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MECP2	ENST00000453960.7	TSL:1 MANE Select	c.418C>G	p.Gln140Glu	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.382C>G	p.Gln128Glu	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
MECP2	ENST00000630151.3	TSL:5	c.382C>G	p.Gln128Glu	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1097568

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26384

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40509

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4032

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841662

Other (OTH)

AF:

0.00

AC:

AN:

46075

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.69

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

-0.61

PhyloP100

5.2

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.78

REVEL

Uncertain

0.55

Sift

Benign

0.46

Sift4G

Benign

1.0

Polyphen

0.0090

Vest4

0.085

MutPred

0.50

Loss of MoRF binding (P = 0.0452)

MVP

0.83

ClinPred

0.60

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.69

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over