X-154030652-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The NM_001110792.2(MECP2):c.1212G>A(p.Glu404Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,189,511 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000098 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.31

Publications

2 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 -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18279219).

BP6

Variant X-154030652-C-T is Benign according to our data. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030652-C-T is described in CliVar as Likely_benign. Clinvar id is 143416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.31 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1212G>A	p.Glu404Glu	synonymous_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1176G>A	p.Glu392Glu	synonymous_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.1212G>A	p.Glu404Glu	synonymous_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.1176G>A	p.Glu392Glu	synonymous_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00000983

AC:

AN:

101736

Hom.:

Cov.:

show subpopulations

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:

0.0000200

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000576

AC:

AN:

173675

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000730

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.19e-7

AC:

AN:

1087775

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356043

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26282

American (AMR)

AF:

0.00

AC:

AN:

35141

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19342

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30160

South Asian (SAS)

AF:

0.00

AC:

AN:

53930

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36361

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

837059

Other (OTH)

AF:

0.00

AC:

AN:

45790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

AF:

0.00000983

AC:

AN:

101736

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

25926

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:

27266

American (AMR)

AF:

0.00

AC:

AN:

9463

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2503

East Asian (EAS)

AF:

0.00

AC:

AN:

3267

South Asian (SAS)

AF:

0.00

AC:

AN:

2154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4951

Middle Eastern (MID)

AF:

0.00

AC:

AN:

227

European-Non Finnish (NFE)

AF:

0.0000200

AC:

AN:

49935

Other (OTH)

AF:

0.00

AC:

AN:

1328

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 05, 2002

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rett syndrome

Benign:1

Aug 14, 2023

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 2.0, this variant is classified as Likely benign. At least the following criteria are met: Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.2

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.084

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.21

MetaRNN

Benign

0.18

MetaSVM

Uncertain

-0.20

PhyloP100

2.3

GERP RS

5.6

Mutation Taster

=41/59

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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