rs62931162

Positions:

• chrX-154031019-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.844delC​(p.Arg282fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.94

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 14 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. Fraction of 0.436 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031019-CG-C is Pathogenic according to our data. Variant chrX-154031019-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 143702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031019-CG-C is described in Lovd as [Pathogenic]. Variant chrX-154031019-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.844delC	p.Arg282fs	frameshift_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.808delC	p.Arg270fs	frameshift_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.844delC	p.Arg282fs	frameshift_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.808delC	p.Arg270fs	frameshift_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Aug 24, 2010	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 22, 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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). (PMID: 11462237, 16225173, 17089071, 36114283, 30536762). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 10767337, 12891673, 17387578, 17089071, 31427717, 30536762, 11245712, 11462237, 17407838, 16225173, 18842453, 16023547, 22476991, 26984561, 10944854, 20139413). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2023	This sequence change creates a premature translational stop signal (p.Arg270Glufs*19) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 217 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with MECP2-related conditions (PMID: 10991688, 16832102, 16965328, 17440498, 21878110). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as '882(C)'. ClinVar contains an entry for this variant (Variation ID: 143702). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Leu386Glnfs*4) have been determined to be pathogenic (PMID: 10814718, 17387578, 19914908). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	curation	RettBASE	Aug 24, 2010	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11402105, 16965328, 16473305, 11738864, 10991688, 11055898, 12567420, 15173251, 32472557, 17440498, 15737703, 16832102) -

MECP2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

The MECP2 c.808delC variant is predicted to result in a frameshift and premature protein termination (p.Arg270Glufs*19). This variant has been reported to be causative for Rett syndrome (Ravn et al. 2011. PubMed ID: 21878110; Venâncio et al. 2007. PubMed ID: 17440498) and it occurred de novo in the patient (Ravn et al. 2011. PubMed ID: 21878110). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Other truncating variants in the 5’ and 3’ surrounding region of this variant have been reported to be pathogenic for Rett syndrome (HGMD database; Wan et al. 1999. PubMed ID: 10577905; Philippe et al. 2006. PubMed ID: 16473305). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs62931162; hg19: chrX-153296470;