chrX-154031137-C-T

Position:

chrX-154031137-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP5BS2

This summary comes from the ClinGen Evidence Repository: The p.Gly231Arg variant in MECP2 (NM_004992.3) is observed in 3 unaffected individuals (PMID:28250423, internal database) (BS2). The p.Gly243Arg variant is reported in one male with autism, and one female with intellectual and developmental disabilities and seizures (PMID:28250423, 24321989) (PS4 not met). The p.Gly231Arg variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Gly231Arg variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294716/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

MECP2
ENST00000453960.7 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:4

Conservation

PhyloP100: 3.57

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP5

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

BS2

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.727G>A	p.Gly243Arg	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.691G>A	p.Gly231Arg	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.727G>A	p.Gly243Arg	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.691G>A	p.Gly231Arg	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

110920

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33092

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:

0.0000569

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098125

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363479

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000270

AC:

AN:

110920

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33092

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000569

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2016	The G231R variant was identified previously in a female with seizures and intellectual and developmental disabilities; however, no additional information was provided to unequivocally demonstrate that it is pathogenic and parental studies were not performed (Sundaram et al., 2014). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G231R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and missense variants in a nearby residue (P225R, P225T) have been reported in RettBASE and the Human Gene Mutation Database in association with Rett syndrome (MECP2 Variation Database; Stenson et al., 2014). However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 16, 2021

- -

Rett syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Dec 08, 2022

The p.Gly231Arg variant in MECP2 (NM_004992.3) is observed in 3 unaffected individuals (PMID: 28250423, internal database) (BS2). The p.Gly243Arg variant is reported in one male with autism, and one female with intellectual and developmental disabilities and seizures (PMID: 28250423, 24321989) (PS4 not met). The p.Gly231Arg variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Gly231Arg variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

- -

History of neurodevelopmental disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2017

In silico models in agreement (benign) ;Other data supporting benign classification -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 17, 2023

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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;T;T

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

1.5

L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.24

N;N;.;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

D;D;.;.

Sift4G

Uncertain

0.032

D;D;.;D

Polyphen

0.65

P;P;.;.

Vest4

0.29

MutPred

0.17

Gain of solvent accessibility (P = 0.0037);.;Gain of solvent accessibility (P = 0.0037);.;

MVP

0.96

ClinPred

0.90

GERP RS

5.5

Varity_R

0.35

gMVP

0.48

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