X-154031243-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4BP6_ModerateBP7BS2

The NM_001110792.2(MECP2):c.621C>A(p.Gly207Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,209,939 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G207G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.85

Publications

1 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40931362).

BP6

Variant X-154031243-G-T is Benign according to our data. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031243-G-T is described in CliVar as Likely_benign. Clinvar id is 2715574.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=2.85 with no splicing effect.

BS2

High AC in GnomAdExome4 at 5 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.621C>A	p.Gly207Gly	synonymous_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.585C>A	p.Gly195Gly	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.621C>A	p.Gly207Gly	synonymous_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.585C>A	p.Gly195Gly	synonymous_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111689

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1098250

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

842137

Other (OTH)

AF:

0.0000217

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111689

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33881

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30630

American (AMR)

AF:

0.00

AC:

AN:

10665

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2651

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

53045

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MECP2-related disorder

Benign:1

Nov 04, 2021

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

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.7

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.071

T;T

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.45

T;T

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

0.72

PhyloP100

2.8

REVEL

Uncertain

0.38

Sift4G

Benign

1.0

T;T

Vest4

0.43

MutPred

0.42

Gain of solvent accessibility (P = 0.0097);.;

MVP

0.96

ClinPred

0.23

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=86/14

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over