rs1557136013

Positions:

• chrX-154030783-TCTCCTTGCTTTTCCGCCCAGGGCTCTTACAGGTCTTCAGTCCTTTCCCGCTCTTCTCACCGAGGGTGGACACCAGCAGGGGCTTCACCACTTCCTTGACCTCGATGCTGACCGTCTCCCGGGTCTTGCGCTTCTTGATGGGGAGTACGGTCTCCTGCACAGATCGGATAGAAGA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.907_1080del​(p.Ile305_Ser362del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: MECP2 NM_001110792.2 inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 4.80

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001110792.2.
• PP5: Variant X-154030783-TCTCCTTGCTTTTCCGCCCAGGGCTCTTACAGGTCTTCAGTCCTTTCCCGCTCTTCTCACCGAGGGTGGACACCAGCAGGGGCTTCACCACTTCCTTGACCTCGATGCTGACCGTCTCCCGGGTCTTGCGCTTCTTGATGGGGAGTACGGTCTCCTGCACAGATCGGATAGAAGA-T is Pathogenic according to our data. Variant chrX-154030783-TCTCCTTGCTTTTCCGCCCAGGGCTCTTACAGGTCTTCAGTCCTTTCCCGCTCTTCTCACCGAGGGTGGACACCAGCAGGGGCTTCACCACTTCCTTGACCTCGATGCTGACCGTCTCCCGGGTCTTGCGCTTCTTGATGGGGAGTACGGTCTCCTGCACAGATCGGATAGAAGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189732.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030783-TCTCCTTGCTTTTCCGCCCAGGGCTCTTACAGGTCTTCAGTCCTTTCCCGCTCTTCTCACCGAGGGTGGACACCAGCAGGGGCTTCACCACTTCCTTGACCTCGATGCTGACCGTCTCCCGGGTCTTGCGCTTCTTGATGGGGAGTACGGTCTCCTGCACAGATCGGATAGAAGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.907_1080del	p.Ile305_Ser362del	inframe_deletion	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.871_1044del	p.Ile293_Ser350del	inframe_deletion	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000303391.11	c.871_1044del	p.Ile293_Ser350del	inframe_deletion	4/4	1	NM_004992.4	ENSP00000301948	P1
MECP2	ENST00000453960.7	c.907_1080del	p.Ile305_Ser362del	inframe_deletion	3/3	1	NM_001110792.2	ENSP00000395535

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 13, 2022	The p.Ile293_Ser350del variant in MECP2 (NM_004992.3) causes an in-frame deletion of 58 amino acids in a non-repeat region of MECP2, which results in a deletion of greater than 10% of the total protein length (PM4_strong). The p.Ile293_Ser350del variant occurs in the well-characterized transcription repression functional domain of the MECP2 gene (PM1). The p.Ile293_Ser350del variant has been observed in at least 2 individuals with Rett syndrome or atypical Rett syndrome (PMID 22277191, internal database - Invitae) (PS4_supporting). In summary, the p.Ile293_Ser350del variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM4_strong, PM1, PS4_supporting). -
Pathogenic, no assertion criteria provided	curation	RettBASE	Sep 27, 2012	- -
Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 25, 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: Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). Protein length changes due to in-frame deletions/insertions in a non-repeat region (PM4). 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).(ClinVar Variation ID: 189732, PMID 22277191) -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

This variant, c.871_1044del, results in the deletion of 58 amino acid(s) of the MECP2 protein (p.Ile293_Ser350del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with atypical Rett syndrome (PMID: 22277191). ClinVar contains an entry for this variant (Variation ID: 189732). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro302His) have been determined to be pathogenic (PMID: 10944854, 15737703, 16225173). 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. -

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: rs1557136013; hg19: chrX-153296234;