rs61750245

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001110792.2(MECP2):c.855G>T(p.Gly285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,210,680 control chromosomes in the GnomAD database, including 1 homozygotes. There are 227 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G285G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., 17 hem., cov: 23)

Exomes 𝑓: 0.00054 ( 1 hom. 210 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.132

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant X-154031009-C-A is Benign according to our data. Variant chrX-154031009-C-A is described in ClinVar as [Benign]. Clinvar id is 143706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031009-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.132 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000569 (64/112491) while in subpopulation AMR AF= 0.000836 (9/10761). AF 95% confidence interval is 0.0006. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.855G>T	p.Gly285=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.819G>T	p.Gly273=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.855G>T	p.Gly285=	synonymous_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.819G>T	p.Gly273=	synonymous_variant	4/4	1	NM_004992.4	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000569

AC:

AN:

112438

Hom.:

Cov.:

AF XY:

0.000491

AC XY:

AN XY:

34596

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000837

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000485

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.000790

Gnomad OTH

AF:

0.00198

GnomAD3 exomes

AF:

0.000461

AC:

AN:

182177

Hom.:

AF XY:

0.000490

AC XY:

AN XY:

67413

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000313

Gnomad NFE exome

AF:

0.000874

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000539

AC:

592

AN:

1098189

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

210

AN XY:

363563

show subpopulations

Gnomad4 AFR exome

AF:

0.0000757

Gnomad4 AMR exome

AF:

0.000199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.000247

Gnomad4 NFE exome

AF:

0.000660

Gnomad4 OTH exome

AF:

0.000325

GnomAD4 genome

AF:

0.000569

AC:

AN:

112491

Hom.:

Cov.:

AF XY:

0.000490

AC XY:

AN XY:

34659

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.000836

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000485

Gnomad4 NFE

AF:

0.000790

Gnomad4 OTH

AF:

0.00195

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000540

EpiCase

AF:

0.00120

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rett syndrome

Benign:3

Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 2023	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 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 2.0 (BA1). -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 01, 2015	The variant of interest causes a synonymous change with 3/5 in silico programs predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 48/85990 (1/1791 including 18 hemizygotes), which exceeds the maximum expected allele frequency for a pathogenic MECP2 variant. The variant of interest has been reported in affected individuals via publications and reputable clinical laboratories/databases with a classification of "benign/polymorphism." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

not specified

Benign:2

Benign, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2017

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2021

This variant is classified as 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_noAF

Benign

-0.51

CADD

Benign

1.7

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over