rs267608642

Positions:

• chrX-154030367-T-C
• chrX-154030367-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS4_Supporting PM4_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.*487Trpext*27 variant in MECP2 (NM_004992.3) occurs at the stop codon and causes a change in the length of the protein and an elongated mRNA transcript of MECP2 (PM4_strong). The p.*487Trpext*27 variant has been observed in at least 2 individuals with features of Rett syndrome (PMID 21807996, internal database - Invitae) (PS4_supporting). The p.*487Trpext*27 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.*487Trpext*27 variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM4_strong, PS4_supporting, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170257/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 stop_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 6.23

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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	c.1497A>G	p.Ter499Trpext*?	stop_lost	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1461A>G	p.Ter487Trpext*?	stop_lost	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1497A>G	p.Ter499Trpext*?	stop_lost	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1461A>G	p.Ter487Trpext*?	stop_lost	4/4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000628176	c.*833A>G		3_prime_UTR_variant	5/5	3		ENSP00000486978.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 15, 2024	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: Protein length changes due to stop-loss variant (PM4_Strong). This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting). (PMID: 21807996, ClinVar Variation ID: 143490). -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 11, 2022	The p.*487Trpext*27 variant in MECP2 (NM_004992.3) occurs at the stop codon and causes a change in the length of the protein and an elongated mRNA transcript of MECP2 (PM4_strong). The p.*487Trpext*27 variant has been observed in at least 2 individuals with features of Rett syndrome (PMID 21807996, internal database - Invitae) (PS4_supporting). The p.*487Trpext*27 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.*487Trpext*27 variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM4_strong, PS4_supporting, PM2_supporting). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2020

This variant has been observed in individual(s) with clinical features of Rett syndrome (PMID: 21807996). ClinVar contains an entry for this variant (Variation ID: 143490). This variant is not present in population databases (ExAC no frequency). This sequence change disrupts the translational stop signal of the MECP2 mRNA. It is expected to extend the length of the MECP2 protein by 27 additional amino acid residues. This variant results in an extension of the MECP2 protein. Other variant(s) that result in a similarly extended protein product (p.*487Serext*27) have been determined to be pathogenic (PMID: 10814719, 11469283). This suggests that these extensions are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Mar 31, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Benign	0.89
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.38
GERP RS		5.8

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

Other links and lift over

dbSNP: rs267608642; hg19: chrX-153295818;