rs61754435

Positions:

chrX-154032416-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro56= (NM_004992.3) variant in MECP2 is 0.231% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro56= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170266/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 5 hem., cov: 24)

Exomes 𝑓: 0.00017 ( 1 hom. 89 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: -1.48

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 -8 ACMG points.

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.204C>T	p.Pro68=	synonymous_variant	2/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.168C>T	p.Pro56=	synonymous_variant	3/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.204C>T	p.Pro68=	synonymous_variant	2/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.168C>T	p.Pro56=	synonymous_variant	3/4	1	NM_004992.4	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000124

AC:

AN:

113152

Hom.:

Cov.:

AF XY:

0.000170

AC XY:

AN XY:

35300

show subpopulations

Gnomad AFR

AF:

0.000128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000924

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00107

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000112

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000290

AC:

AN:

183012

Hom.:

AF XY:

0.000340

AC XY:

AN XY:

67602

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000721

Gnomad SAS exome

AF:

0.00231

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000169

AC:

186

AN:

1097992

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

AN XY:

363354

show subpopulations

Gnomad4 AFR exome

AF:

0.000227

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000993

Gnomad4 SAS exome

AF:

0.00216

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

AF:

0.000115

AC:

AN:

113207

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

35363

show subpopulations

Gnomad4 AFR

AF:

0.000128

Gnomad4 AMR

AF:

0.0000923

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000714

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000112

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000680

EpiCase

AF:

0.000436

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2015	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. -
Benign, no assertion criteria provided	curation	RettBASE	Feb 03, 2006	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 30, 2016	- -

Rett syndrome

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 13, 2021	The allele frequency of the p.Pro56= (NM_004992.3) variant in MECP2 is 0.231% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro56= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). -
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). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

MECP2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.4

DANN

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

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