NM_001110792.2:c.788C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP6_Moderate

The NM_001110792.2(MECP2):c.788C>T(p.Pro263Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,067 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. P263R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 6.17

Publications

3 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 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 8 uncertain in NM_001110792.2

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant X-154031076-G-A is Benign according to our data. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031076-G-A is described in CliVar as Likely_benign. Clinvar id is 143683.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.788C>T	p.Pro263Leu	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.752C>T	p.Pro251Leu	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.788C>T	p.Pro263Leu	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.752C>T	p.Pro251Leu	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098067

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363437

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26398

American (AMR)

AF:

0.00

AC:

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54143

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841994

Other (OTH)

AF:

0.00

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

Alfa

AF:

0.0000457

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 15, 2002

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Rett syndrome

Benign:1

Mar 20, 2024

Centre for Population Genomics, CPG

Significance:Likely 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 3.0, this variant is classified as likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). PMID 10944854 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Benign

1.9

L;.;.;.

PhyloP100

6.2

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.9

D;D;.;.

REVEL

Uncertain

0.51

Sift

Uncertain

0.0030

D;D;.;.

Sift4G

Uncertain

0.0040

D;D;.;D

Polyphen

0.99

D;D;.;.

Vest4

0.49

MutPred

0.13

Loss of glycosylation at P251 (P = 0.0209);.;Loss of glycosylation at P251 (P = 0.0209);.;

MVP

0.97

ClinPred

0.98

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.88

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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