rs267608470

Variant names:

• chrX-154031436-G-T
• rs267608470
• NM_001110792.2:c.428C>A

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PM1 PS2

This summary comes from the ClinGen Evidence Repository: The p.Ala131Asp variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage confirmed) in an individual with features of Rett syndrome (internal database - GeneDx) and reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with features of Rett syndrome (PMID 15737703 and 26984561) (PS2_Very strong). The p.Ala131Asp variant occurs in the well-characterized Methyl-DNA binding [MDB] functional domain of the MECP2 (PM1). The p.Ala131Asp variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Ala131Asp variant in MECP2 (NM_004992.3) is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_Very strong, PM1, PM2_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270384/MONDO:0010726/036

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.47

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]

ACMG classification

Verdict is Pathogenic. Variant got 7 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.428C>A	p.Ala143Asp	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.392C>A	p.Ala131Asp	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.428C>A	p.Ala143Asp	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.392C>A	p.Ala131Asp	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Feb 18, 2008

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Aug 30, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Ala131Asp variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage confirmed) in an individual with features of Rett syndrome (internal database - GeneDx) and reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with features of Rett syndrome (PMID 15737703 and 26984561) (PS2_Very strong). The p.Ala131Asp variant occurs in the well-characterized Methyl-DNA binding [MDB] functional domain of the MECP2 (PM1). The p.Ala131Asp variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Ala131Asp variant in MECP2 (NM_004992.3) is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_Very strong, PM1, PM2_Supporting). -

Jan 10, 2024

Centre for Population Genomics, CPG

Significance: Likely pathogenic

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 pathogenic. At least the following criteria are met: Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID: 15737703 Computational prediction analysis tools suggests a deleterious impact (REVEL score 0.91>= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 15737703 This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:1

Apr 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 15737703, 26984561, 21831886, 12843318) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;T;D;D;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.0	L;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N;.;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;.;.;.;.;.
Sift4G	Uncertain	0.014	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.85
MutPred		0.84		Gain of ubiquitination at K135 (P = 0.0444);.;Gain of ubiquitination at K135 (P = 0.0444);.;Gain of ubiquitination at K135 (P = 0.0444);.;.;
MVP		1.0
ClinPred		0.93	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs267608470; hg19: chrX-153296887;