X-154032431-G-C

Variant names:

• chrX-154032431-G-C
• rs267608432
• NM_001110792.2:c.189C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.His51Gln variant in MECP2 (NM_004992.4) is absent from gnomAD v4.1 (PM2_Supporting). However, the p.His51Gln variant is observed in at least 1 unaffected individual (PMID 21300488) (BS2_supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.His51Gln variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) LINK:https://erepo.genome.network/evrepo/ui/classification/CA170260/MONDO:0010726/036

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:1
• Conservation: PhyloP100: 2.04
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: 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 rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.189C>G	p.His63Gln	missense_variant	Exon 2 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.153C>G	p.His51Gln	missense_variant	Exon 3 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.189C>G	p.His63Gln	missense_variant	Exon 2 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.153C>G	p.His51Gln	missense_variant	Exon 3 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097987 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363349

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841972

Other (OTH) AF: 0.00 AC: 0 AN: 46093

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Uncertain:1 Benign:1

Jan 11, 2024

Centre for Population Genomics, CPG

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 3.0, this variant is classified as likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). This variant did not segregate in an affected family member (BS4_Supporting) PMID 21300488 -

May 07, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The p.His51Gln variant in MECP2 (NM_004992.4) is absent from gnomAD v4.1 (PM2_Supporting). However, the p.His51Gln variant is observed in at least 1 unaffected individual (PMID 21300488) (BS2_supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.His51Gln variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Mar 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 143493). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MECP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 51 of the MECP2 protein (p.His51Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. -

not specified Uncertain:1

May 18, 2012

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Uncertain:1

Aug 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a polymorphism in an unaffected individual in published literature (Khajuria et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21300488) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;T;T;T;T;T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.65	T;T;T;T;T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.81	L;.;.;.;.;.;.
PhyloP100		2.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N;N;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D;.;.;.;.;.
Sift4G	Benign	0.42	T;T;T;T;.;T;T
Polyphen		0.079	B;B;.;.;.;.;.
Vest4		0.61
MutPred		0.075		Gain of solvent accessibility (P = 0.0837);.;Gain of solvent accessibility (P = 0.0837);.;Gain of solvent accessibility (P = 0.0837);.;.;
MVP		1.0
ClinPred		0.49	T
GERP RS		5.8
PromoterAI		0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.12
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs267608432; hg19: chrX-153297882;