X-154031127-G-C

Position:

chrX-154031127-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala234Gly variant in MECP2 (NM_004992.3) is 0.26% in Ashkenazi Jewish 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). The p.Ala234Gly variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.Ala234Gly variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294719/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000058 ( 0 hom. 23 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:5

Conservation

PhyloP100: 1.56

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 -12 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.737C>G	p.Ala246Gly	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.701C>G	p.Ala234Gly	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.737C>G	p.Ala246Gly	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.701C>G	p.Ala234Gly	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000542

AC:

AN:

110702

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

33010

show subpopulations

Gnomad AFR

AF:

0.0000660

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000761

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000379

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000125

AC:

AN:

183356

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

67854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00267

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000583

AC:

AN:

1098226

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363580

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00232

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000131

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.0000542

AC:

AN:

110702

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

33010

show subpopulations

Gnomad4 AFR

AF:

0.0000660

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000761

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000379

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000227

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	- -

Rett syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Dec 08, 2022

The allele frequency of the p.Ala234Gly variant in MECP2 (NM_004992.3) is 0.26% in Ashkenazi Jewish 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). The p.Ala234Gly variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.Ala234Gly variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2017

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2022

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

0.076

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.;T;T

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.043

T;T;T;T

MetaSVM

Uncertain

-0.071

MutationAssessor

Benign

1.4

L;.;.;.

MutationTaster

Benign

0.72

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.48

N;N;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.36

T;T;.;.

Sift4G

Benign

0.25

T;T;.;T

Polyphen

0.92

P;P;.;.

Vest4

0.092

MutPred

0.084

Gain of catalytic residue at P230 (P = 0.0924);.;Gain of catalytic residue at P230 (P = 0.0924);.;

MVP

0.97

ClinPred

0.12

GERP RS

4.6

Varity_R

0.067

gMVP

0.41

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