X-154030753-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_001110792.2(MECP2):c.1111T>C(p.Ser371Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000053 in 1,207,825 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 12/21 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. S371F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000054 ( 0 hom. 14 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.978

Publications

4 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14675197).

BP6

Variant X-154030753-A-G is Benign according to our data. Variant chrX-154030753-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1111T>C	p.Ser371Pro	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.1075T>C	p.Ser359Pro	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.1111T>C	p.Ser371Pro	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.1075T>C	p.Ser359Pro	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.0000454

AC:

AN:

110221

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

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:

0.0000380

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000828

AC:

AN:

181230

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000475

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000538

AC:

AN:

1097604

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

363060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26382

American (AMR)

AF:

0.000455

AC:

AN:

35161

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19358

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40468

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4109

European-Non Finnish (NFE)

AF:

0.0000451

AC:

AN:

841757

Other (OTH)

AF:

0.0000651

AC:

AN:

46061

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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

AF:

0.0000454

AC:

AN:

110221

Hom.:

Cov.:

AF XY:

0.0000613

AC XY:

AN XY:

32611

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30164

American (AMR)

AF:

0.000286

AC:

AN:

10481

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3519

South Asian (SAS)

AF:

0.00

AC:

AN:

2573

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

52564

Other (OTH)

AF:

0.00

AC:

AN:

1478

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0338994), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00741

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 05, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The MECP2 c.1075T>C (p.Ser359Pro) variant involves the alteration of a non-conserved nucleotide, changing a small, polar amino acid (S) to a medium, hydrophobic residue (P). 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). S359 has been shown to be phosphorylated in human skin fibroblasts, and phosphorylation of MECP2 has been shown to modulate its binding affinity, gene expression, and cellular adaptations to stimuli and neuronal plasticity (Bellini_2014). However, the functional impact of replacing S359 with a proline residue has not been studied. S359 is located within the C-terminal domain, whereas most classic RTT-causing mutations lie within the methyl-CpG-binding (MBD) or transcriptional-repression (TRD) functional domains (Bienvenu_ 2002). This variant was found in 17/198183 control chromosomes at a frequency of 0.0000858, which is approximately 10 times the estimated maximal expected allele frequency of a pathogenic MECP2 variant (0.0000083), suggesting this variant is likely a benign polymorphism. This variant has been cited in both patients and controls. A family co-segregation study showed that the variant was found in the healthy mother, healthy maternal aunt, and 3 healthy cousins (1 male and 2 females) of an intellectually disabled male (Moncla_2002), suggesting that S359P is not a pathogenic variant regardless of its potential functional impact. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.

Jan 21, 2008

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

Aug 14, 2015

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.

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

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Rett syndrome

Benign:1

Mar 13, 2024

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 3.0, 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 3.0 (BA1).

Inborn genetic diseases

Benign:1

May 18, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

MECP2-related disorder

Benign:1

Sep 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.29

T;.

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.4

L;.

PhyloP100

0.98

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.82

N;N

REVEL

Uncertain

0.49

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.40

T;T

Vest4

0.12

ClinPred

0.042

GERP RS

2.7

Varity_R

0.29

gMVP

0.58

Mutation Taster

=90/10

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over