rs267608607

Positions:

• chrX-154030637-CTCGGAGCTCTCGGGCTCAGGTGGAGG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000453960.7(MECP2):​c.1201_1226del​(p.Pro401GlyfsTer7) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P401P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 17)
• Consequence: MECP2 ENST00000453960.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.66

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 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 76 pathogenic variants in the truncated region.
• PP5: Variant X-154030637-CTCGGAGCTCTCGGGCTCAGGTGGAGG-C is Pathogenic according to our data. Variant chrX-154030637-CTCGGAGCTCTCGGGCTCAGGTGGAGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 143409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030637-CTCGGAGCTCTCGGGCTCAGGTGGAGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1201_1226del	p.Pro401GlyfsTer7	frameshift_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1165_1190del	p.Pro389GlyfsTer7	frameshift_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000303391.11	c.1165_1190del	p.Pro389GlyfsTer7	frameshift_variant	4/4	1	NM_004992.4	ENSP00000301948	P1
MECP2	ENST00000453960.7	c.1201_1226del	p.Pro401GlyfsTer7	frameshift_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000407218.5	c.*537_*562del		3_prime_UTR_variant	4/4	5		ENSP00000384865
MECP2	ENST00000628176.2	c.*537_*562del		3_prime_UTR_variant	5/5	3		ENSP00000486978

Frequencies

GnomAD3 genomes Cov.: 17

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 17

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 2023	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 2.0, this variant is classified as pathogenic. The following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). 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: 16473305, 10814719). -
Pathogenic, no assertion criteria provided	curation	RettBASE	Jan 21, 2008	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the MECP2 protein. Other variant(s) that disrupt this region (p.Gln406*) have been determined to be pathogenic (PMID: 10986043, 14560307, 22476991). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with Rett syndrome (PMID: 10814719, 11768391, 16473305, 19914908). ClinVar contains an entry for this variant (Variation ID: 143409). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MECP2 gene (p.Pro389Glyfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acids of the MECP2 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608607; hg19: chrX-153296088;